Amide derivatives for the treatment of diseases mediated by cytokines

ABSTRACT

The invention concerns the use of amide derivatives of formula (I) wherein: R 1  and R 2  are substituents such as hydroxy, C 1-6 alkoxy, mercapto, C 1-6 alkylthio, amino, C 1-6 alkylamino and di-(C 1-6 alkyl)amino; m and p are independently 0-3; R 3  is C 1-4 alkyl; q is 0-4; and R 4  is aryl or cycloalkyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines.

[0001] This invention concerns the use of certain amide derivatives asinhibitors of cytokine mediated disease. The invention also concernscertain novel amide derivatives, processes for the manufacture of saidnovel amide derivatives, pharmaceutical compositions containing them andtheir use in therapeutic methods, for example by virtue of inhibition ofcytokine mediated disease.

[0002] The amide derivatives disclosed in the present invention areinhibitors of the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the compounds of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, TNFα and IL-1 have been implicated in the cell signallingcascade which is believed to contribute to the pathology of diseasestates such as inflammatory and allergic diseases and cytokine-inducedtoxicity. It is also known that, in certain cellular systems. TNFαproduction precedes and mediates the production of other cytokines suchas IL-1.

[0003] Abnormal levels of cytokines have also been implicated in, forexample, the production of physiologically-active eicosanoids such asthe prostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

[0004] Cytokines are also believed to be implicated in the productionand development of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis allergic rhinitis and adult respiratorydistress syndrome), and in the production and development of variouscardiovascular and cerebrovascular disorders such as myocardialinfarction, the formation of atherosclerotic plaques, hypertension,platelet aggregation, angina, stroke, reperfusion injury, vascularinjury including restenosis and peripheral vascular disease, and, forexample, various disorders of bone metabolism such as osteoporosis(including senile and postmenopausal osteoporosis), Paget's disease,bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis,osteoperosis and periodontitis, and the abnormal changes in bonemetabolism which may accompany rheumatoid arthritis and osteoarthritis.Excessive cytokine production has also been implicated in mediatingcertain complications of bacterial, fungal and/or viral infections suchas endotoxic shock, septic shock and toxic shock syndrome and inmediating certain complications of CNS surgery or injury such asneurotrauma and ischaemic stroke. Excessive cytokine production has alsobeen implicated in mediating or exacerbating the development of diseasesinvolving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis,renal fibrosis, the cachexia found in certain chronic diseases such asmalignant disease and acquired immune deficiency syndrome (AIDS), tumourinvasiveness and tumour metastasis and multiple sclerosis.

[0005] Evidence of the central role played by TNFα in the cellsignalling cascade which gives rise to rheumatoid arthritis is providedby the efficacy in clinical studies of antibodies of TNFα (The Lancet,1994, 344, 1125 and British Journal of Rheumatology, 1995, 34, 334).

[0006] Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

[0007] Without wishing to imply that the compounds disclosed in thepresent invention possess pharmacological activity only by virtue of aneffect on a single biological process, it is believed that the compoundsinhibit the effects of cytokines by virtue of inhibition of the enzymep38 kinase. P38 kinase, otherwise known as cytokine suppressive bindingprotein (hereinafter CSBP) and reactivating kinase (hereinafter RK), isa member of the mitogen-activated protein (hereinafter MAP) kinasefamily of enzymes which is known to be activated by physiological stresssuch as that induced by ionising radiation, cytotoxic agents, andtoxins, for example endotoxins such as bacterial lipopolysaccharide, andby a variety of agents such as the cytokines, for example TNFα and IL-1.It is known that p38 kinase phosphorylates certain intracellularproteins which are involved in the cascade of enzymatic steps whichleads to the biosynthesis and excretion of cytokines such as TNFα andIL-1. Known inhibitors of p38 kinase have been reviewed by G J Hanson inExpert Opinions on Therapeutic Patents, 1997, 7, 729-733, p38 kinase isknown to exist in isoforms identified as p38α and p38β.

[0008] The compounds disclosed in the present invention are inhibitorsof the production of cytokines such as TNF, in particular of TNFα, andvarious interleukins, in particular IL-1.

[0009] According to one aspect of the present invention there isprovided the use of a compound of the Formula I

[0010] wherein:

[0011] R¹ and R², which may be the same or different are selected fromhydroxy, C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulphonyl,arylsulphonyl, C₁₋₆alkylaminosulphonyl, di-(C₁₋₆alkyl)aminosulphonyl,nitro, cyano, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,C₁₋₆alkanoylamino, C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo, trifluoromethyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkoxy, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl andheterocyclylC₁₋₆alkyl;

[0012] m and p, are independently 0-3, and when m and/or p is 2 or 3each R group may be the same or different;

[0013] R³ is C₁₋₄alkyl;

[0014] q is 0-4;

[0015] R⁴ is aryl or cycloalkyl wherein R⁴ is optionally substitutedwith up to 3 substituents having any value defined for R¹;

[0016] or a pharmaceutically-acceptable salt or in vivo cleavable esterthereof in the manufacture of a medicament for use in the treatment ofdiseases or medical conditions mediated by cytokines.

[0017] In a further aspect the present invention provides a method oftreating diseases or medical conditions mediated by cytokines whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof.

[0018] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein the treatment of diseases or medical conditions mediated by TNF,IL-1, IL-6 or IL-8.

[0019] In a further aspect the present invention provides a method oftreating diseases or medical conditions mediated by TNF, IL-1, IL-6 orIL-8 which comprises administering to a warm-blooded animal an effectiveamount of a compound of the Formula I, or a pharmaceutically-acceptablesalt or in vivo cleavable ester thereof.

[0020] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein the treatment of diseases or medical conditions mediated by TNF.

[0021] In a further aspect the present invention provides a method oftreating diseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt or in vivocleavable ester thereof.

[0022] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein inhibiting TNF, IL-1, IL-6 or IL-8.

[0023] In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt or in vivo cleavable esterthereof.

[0024] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein inhibiting TNF.

[0025] In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of a compound of the Formula I, or apharmaceutically-acceptable salt or in vivo cleavable ester thereof.

[0026] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein the treatment of diseases or medical conditions mediated by p38kinase.

[0027] In a further aspect the present invention provides a method oftreating diseases or medical conditions mediated by p38 kinase whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof.

[0028] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein the production of a p38 kinase inhibitory effect.

[0029] In a further aspect the present invention provides a method ofproviding a p38 kinase inhibitory effect which comprises administeringto a warm-blooded animal an effective amount of a compound of theFormula I, or a pharmaceutically-acceptable salt or in vivo cleavableester thereof.

[0030] In a further aspect the present invention provides the use of acompound of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, in the manufacture of a medicament for usein the treatment of rheumatoid arthritis, asthma, irritable boweldisease, multiple sclerosis, AIDS, septic shock, ischaemic heart diseaseor psoriasis.

[0031] In a further aspect the present invention provides a method oftreating rheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, ischaemic heart disease or psoriasiswhich comprises administering to a warm-blooded animal an effectiveamount of a compound of the Formula I, or a pharmaceutically-acceptablesalt or in vivo cleavable ester thereof.

[0032] Certain compounds falling within the scope of Formula (I) areknown to upregulate LDL receptors (Brown et al. in Atherosclerosis(1994) 109:113-114, Halley et al. in J. Med. Chem., (1996) 39:3343-3356). The compounds listed immediately hereinafter were disclosedin that J. Med. Chem, paper and fall within the scope of the compounddefinition disclosed hereinbefore:—

[0033]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0034]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetoxybenzamide,

[0035] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]benzamide,

[0036]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,

[0037]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide,

[0038]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide,

[0039]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxymethylbenzamide,

[0040] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-nitrobenzamide,

[0041] N-[5-(3-cyclohexylproplonamido)-2-methylphenyl]-4-aminobenzamide,

[0042] N-[5-(2-cyclohexylacetamido)-2-methylphenyl]-4-acetoxybenzamide,

[0043]N-[5-(4-cyclohexylbutylrylamino)-2-methylphenyl]-4-hydroxybenzamide,

[0044]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0045] N-[5-(3-phenylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0046]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide,

[0047] N-[5-(3-phenylpropionamido)-2-methylphenyl]-4-acetoxybenzamideand

[0048]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-acetoxybenzamide.

[0049] From these compounds the following representative examples havenow been found to possess p38 kinase inhibitory activity:—

[0050]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]4-hydroxybenzamide,

[0051]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,

[0052]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]4-hydroxybenzamide,

[0053] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-aminobenzamideand

[0054]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]4-hydroxybenzamide.

[0055] Copending International Patent Application PCT/GB97/03 102 whichgave rise on May 28, 1998 to International Application Publication No.WO 98/22103 concerns certain bisamide derivatives which are stated topossess inhibitory activity against the enzyme raf kinase and thereby tobe useful in the treatment of diseases such as cancer. The compoundsdisclosed therein as examples are listed immediately hereinafter andfall within the scope of the compound definition disclosedhereinbefore:—

[0056]N-[5-(2-bicyclo[2.2.1]hept-2-ylacetamido)-2-methylphenyl]-4-hydroxybenzamide,

[0057]N-{5-[2-(3,4-dichlorophenyl)acetamido]-2-methylphenyl}-4-hydroxybenzamideand

[0058]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide.These compounds have now been found to possess p38 kinase inhibitoryactivity.

[0059] In a further aspect the present invention provides a compound ofthe Formula I as defined hereinbefore for use in a method of treatmentof the human or animal body by therapy, in particular for use in thetreatment of diseases or medical conditions mediated by cytokines and,more particularly, for use in inhibiting TNF, except that

[0060]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0061]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetoxybenzamide,

[0062] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]benzamide,

[0063]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,

[0064]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide,

[0065]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide,

[0066]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxymethylbenzamide,

[0067] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-nitrobenzamide,

[0068] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-aminobenzamide,

[0069] N-[5-(2-cyclohexylacetamido)-2-methylphenyl]-4-acetoxybenzamide,

[0070]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide,

[0071]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0072] N-[5-(3-phenylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0073]N-[5-(2-bicyclo[2.2.1]hept-2-ylacetamido)-2-methylphenyl]4-hydroxybenzamide,

[0074]N-{5-[2-(3,4-dichlorophenyl)acetamido]-2-methylphenyl}-4-hydroxybenzamide,

[0075]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide,

[0076]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide,

[0077] N-[5-(3-phenylpropionamido)-2-methylphenyl]-4-acetoxybenzamideand

[0078]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-acetoxybenzamide areexcluded.

[0079] Certain other compounds within the scope of Formula I are knownoutside the pharmaceutical field:—

[0080] (a) Japanese Patent Application No. 04065513 (Chemical Abstracts,117, 50742) discloses the compoundN-[5-(4-carbamoylbenzamido)-2-methylphenyl]-4-carbamoylbenzamide as achemical intermediate;

[0081] (b) Japanese Patent Application No. 62198852 (Chemical Abstracts,109. 14765) discloses the compoundN-[5-(3,4.5-trihydroxybenzamido)-2-methylphenyl]-3,4,5-trihydroxybenzamideas a chemical intermediate;

[0082] (c) U.S. Pat. No. 4,410,681 (Chemical Abstracts, 100, 52612) andU.S. Pat. No. 4,367,328 (Chemical Abstracts 98, 144515) each disclosethe compoundN-[5-(2-hydroxybenzamido)-2-methylphenyl]-2-hydroxybenzamide as achemical intermediate;

[0083] (d) Japanese Patent Application No. 53079835 (Chemical Abstracts,89, 147671) discloses the compoundN-{5-[4-carboxy-3-(2-dimethylaminoethoxycarbonyl)benzamido]-2-methylphenyl}-4-carboxy-3-(2-dimethylaminoethoxycarbonyl)benzamideas a chemical intermediate;

[0084] (e) German Patent Application No. DE 2552609 (Chemical Abstracts,85, 192408) discloses the compoundsN-[5-(3-methoxycarbonylbenzamido)-2-methylphenyl]-3-methoxycarbonylbenzamideandN-[5-(4-methoxycarbonylbenzamido)-2-methylphenyl]-4-methoxycarbonylbenzamideas chemical intermediates;

[0085] (f) Japanese Patent Application No. 50105558 (Chemical Abstracts,84, 45269) discloses the compoundN-[5-(4-methoxybenzamido)-2-methylphenyl]-4-methoxybenzamide as achemical intermediate;

[0086] (g) Japanese Patent Application No. 61204221 (Chemical Abstracts,106, 34087) discloses the compoundN-(5-benzamido-2-methylphenyl)benzamide as a chemical intermediate;

[0087] (h) Netherlands Patent Application No. 6514411 (ChemicalAbstracts, 65, 10706f) discloses certain indolizine derivatives asaromatic pigments;

[0088] (i) Chemical Abstracts, 64, 19459g concerns reduction of somealkyl-substituted dinitrobenzenes and discloses the compoundN-(5-benzamido-2-ethylphenyl)benzamide; and

[0089] (j) Chemical Abstracts, 62, 3959d discloses the compoundN-[5-(4-nitrobenzamido)-2-ethylphenyl]-4-nitrobenzamide.

[0090] The reader is directed to these references for general guidanceon synthesis of compounds within the scope of Formula I.

[0091] In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

[0092] “Aryl” in terms such as “aryl”, “arylC₁₋₆alkyl”, “arylsulphonyl”and “arylC₁₋₆alkoxy” typically means phenyl or naphthyl, preferablyphenyl. An “arylC₁₋₆alkyl” group means, for example, arylmethyl or2-arylethyl. An “arylC₁₋₆alkoxy” group means, for example, arylmethoxyor 2-arylethoxy. “Heteroaryl” in the terms “heteroaryl” and“heteroarylC₁₋₆alkyl” means an aromatic mono- or bicyclic 5-10 memberedring with up to five ring heteroatoms selected from nitrogen, oxygen andsulphur. Examples of ‘heteroaryl’ include thienyl, pyrrolyl, furyl,imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl and cinnolinyl. A“heteroarylC₁₋₆alkyl” group means, for example, heteroarylmethyl or2-heteroarylethyl. “Heterocyclyl” in the terms “heterocyclyl” and“heterocyclylC₁₋₆alkyl” means a non-aromatic mono- or bicyclic 5-10membered ring with up to five ring hetero atoms selected from nitrogen,oxygen and sulphur. Examples of ‘heterocyclyl’ include pyrrolinyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, homopiperidinyl,homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl and tetrahydropyrimidinyl. A “heterocyclylC₁₋₆alkyl”group means, for example, heterocyclylmethyl or 2-heterocyclylethyl.“Cycloalkyl” means a non-aromatic mono- or bicyclic 5-10 membered carbonring. Examples of “cycloalkyl” include cyclopentyl, cyclohexyl,cycloheptyl, bicyclo[2.2.1]heptyl and bicyclo[4.4.0]decyl.

[0093] Typical values for other generic groups include: for C₁₋₆alkoxy,for example, methoxy and ethoxy, for C₁₋₆alkylthio, for example,methylthio, for C₁₋₆alkylamino, for example, methylamino, fordi-(C₁₋₆alkyl)amino, for example, dimethylamino, for C₁₋₆alkoxycarbonyl,for example, methoxycarbonyl and ethoxycarbonyl, for C₁₋₆alkylcarbamoyl,for example, methylcarbamoyl, for di-C₁₋₆alkylcarbamoyl, for example,dimethylcarbamoyl, for C₁₋₆alkylsulphonyl, for example, methylsulphonyl,for arylsulphonyl, for example, phenylsulphonyl, forC₁₋₆alkylaminosulphonyl, for example, methylaminosulphonyl, fordi-(C₁₋₆alkyl)aminosulphonyl, for example, dimethylaminosulphonyl, forcyanoC₁₋₆alkyl, for example, cyanomethyl, for hydroxyC₁₋₆alkyl, forexample, hydroxymethyl, for aminoC₁₋₆alkyl, for example, aminomethyl,for C₁₋₆alkanoylamino, for example, formamido and acetamido, forC₁₋₆alkoxycarbonylamino, for example, methoxycarbonylamino, forC₁₋₆alkanoyl, for example, formyl and acetyl, for C₁₋₆alkanoyloxy, forexample, acetoxy, for C₁₋₆alkyl or C₁₋₄alkyl, for example, methyl,ethyl, propyl, isopropyl and tert-butyl, for halo, for example, fluoro,chloro and bromo, for aryl, for example, phenyl for arylC₁₋₆alkyl, forexample, benzyl, and for arylC₁₋₆alkoxy, for example, benzyloxy.

[0094] Any ring in R¹ or R² or any ring in a substituent on R⁴ may beoptionally substituted, for example by up to 3 substituents. Suitablesubstituents include hydroxy, C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio,amino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino, carboxy, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulphonyl,arylsulphonyl, C₁₋₆alkylaminosulphonyl, di-(C₁₋₆alkyl)aminosulphonyl,nitro, cyano, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,C₁₋₆alkanoylamino, C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo and trifluoromethyl. For example, whenR¹ or a substituent on R⁴ is a heterocyclyl or heterocyclylC₁₋₆alkylgroup the heterocyclyl ring may bear up to 3 substituents selected fromhydroxy, C₁₋₆alkoxy, carboxy, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, C₁₋₆alkanoyl, C₁₋₆alkyl, halo andtrifluoromethyl. Examples of such substituted heterocyclyl rings include4-carbamoylpiperidin-1-yl, 4-methylpiperazin-1-yl and4-acetylpiperazin-1-yl.

[0095] It is to be understood that, insofar as certain of the compoundsof Formula I defined above may exist in optically active or racemicforms by virtue of one or more asymmetric carbon atoms, the inventionincludes in its definition any such optically active or racemic formwhich possesses the property of inhibiting cytokines, in particular TNF.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

[0096] Preferably R¹ is hydroxy, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl,carbamoyl, C₁₋₆alkylcarbamoyl, C₁₋₆alkanoylamino, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo, trifluoromethyl, phenyl or phenylC₁₋₆alkoxy.

[0097] Most preferably R¹ is hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoylamino orC₁₋₆alkanoyl.

[0098] Preferably m is 1 or 2.

[0099] Preferably R³ is methyl.

[0100] Preferably R² is carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,C₁₋₆alkylcarbamoyl or di-(C₁₋₆alkyl)carbamoyl.

[0101] Preferably p is 0.

[0102] Preferably R⁴ is phenyl, cyclohexyl or cyclopentyl.

[0103] More preferably R⁴ is phenyl or cyclohexyl.

[0104] Preferred substituents for aryl and cyclohexyl groups in R⁴ arehydroxy, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, carbamoyl, C₁₋₆alkylcarbamoyl,C₁₋₆alkanoylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo,trifluoromethyl, phenyl, phenylC₁₋₆alkoxy, nitro, cyano, amino,C₁₋₆alkylamino or di-(C₁₋₆alkyl)amino.

[0105] More preferably substituents for aryl and cyclohexyl in R⁴ areselected from cyano, dimethylamino, methoxy, ethoxy, fluoro, chloro,nitro and phenyl.

[0106] In a further aspect the present invention provides novelcompounds within the scope of the compounds of the Formula I as definedhereinbefore.

[0107] A particular group of compounds of the invention includes, forexample, amide derivatives of the Formula I, orpharmaceutically-acceptable salts thereof, wherein:—

[0108] (a) q is 1, 2, 3 or 4 and R⁴ is cycloalkyl; and R¹, R², R³, m andp have any of the meanings defined hereinbefore; and

[0109] (b) q is 0 and R⁴ is phenyl which is optionally substituted withup to 3 substituents having any value defined hereinbefore for R¹; andR¹, R², R³, m and p have any of the meanings defined hereinbefore.

[0110] A particular novel compound of the invention is an amidederivative of the Formula I wherein R¹ is hydroxy, methoxy, ethoxy,propoxy, isopropoxy, butoxy, amino, methylamino, dimethylamino, carboxy,methoxycarbonyl, nitro, cyano, acetamido, acetyl, acetoxy, methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, bromo,trifluoromethyl, pyrrolidin-1-yl, piperidino, morpholino,4-thiamorpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-methylhomopiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl;

[0111] m is 1, 2 or 3;

[0112] p is 0;

[0113] R³ is methyl;

[0114] q is 0; and

[0115] R⁴ is phenyl which is optionally substituted with 1 or 2substituents selected from hydroxy, methoxy, ethoxy, amino, methylamino,dimethylamino, methoxycarbonyl, nitro, cyano, acetamido, fluoro, chloro,bromo, trifluoromethyl, phenyl benzyloxy, pyrrolidin-1-yl, piperidino,morpholino, 4-thiamorpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-methylhomopiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl;

[0116] or a pharmaceutically-acceptable salt thereof;

[0117] except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide,

[0118] N-[5-(2-hydroxybenzamido)-2-methylphenyl]-2-hydroxybenzamide,

[0119] N-[5-(4-methoxybenzamido)-2-methylphenyl]-4-methoxybenzamide,

[0120]N-[5-(3-methoxycarbonylbenzamido)-2-methylphenyl]-3-methoxycarbonylbenzamideand

[0121]N-[5-(4-methoxycarbonylbenzamido)-2-methylphenyl]4-methoxycarbonylbenzamideare excluded.

[0122] A preferred novel compound of the invention is an amidederivative of the Formula I wherein R¹ is hydroxy, methoxy, ethoxy,isopropoxy, carboxy, methoxycarbonyl, nitro, cyano, acetyl, acetoxy,methyl, ethyl, propyl, fluoro, chloro or trifluoromethyl;

[0123] m is 1, 2 or 3;

[0124] p is 0;

[0125] R³ is methyl;

[0126] q is 0; and

[0127] R⁴ is phenyl which is optionally substituted with 1 or 2substituents selected from hydroxy, methoxy, amino, methylamino,dimethylamino, nitro, cyano, fluoro, chloro, bromo, trifluoromethyl andbenzyloxy;

[0128] or a pharmaceutically-acceptable salt thereof;

[0129] except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide,

[0130] N-[5-(2-hydroxybenzamido)-2-methylphenyl]-2-hydroxybenzamide and

[0131] N-[5-(4-methoxybenzamido)-2-methylphenyl]-4-methoxybenzamide areexcluded.

[0132] A more preferred novel compound of the invention is an amidederivative of the Formula I

[0133] wherein

[0134] R¹ is hydroxy, methoxy, carboxy or acetoxy;

[0135] m is 1 or 2;

[0136] p is 0;

[0137] R³ is methyl;

[0138] q is 0; and

[0139] R⁴ is phenyl which is optionally substituted with a substituentselected from hydroxy, dimethylamino, cyano and benzyloxy;

[0140] or a pharmaceutically-acceptable salt thereof;

[0141] except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide and

[0142] N-[5-(2-hydroxybenzamido)-2-methylphenyl]-2-hydroxybenzamide areexcluded.

[0143] A further preferred novel compound of the invention is an amidederivative of the Formula I

[0144] wherein R¹ is hydroxy, methoxy, ethoxy, propoxy, isopropoxy,butoxy, amino, methylamino, dimethylamino, carboxy, methoxycarbonyl,nitro, cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, fluoro, chloro, bromo, trifluoromethyl,pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl;

[0145] m is 1, 2 or 3;

[0146] p is 0;

[0147] R³ is methyl;

[0148] q is 1, 2, 3 or 4; and

[0149] R⁴ is cyclopentyl or cyclohexyl;

[0150] or a pharmaceutically-acceptable salt thereof;

[0151] except thatN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0152]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]4-acetoxybenzamide,

[0153]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,

[0154]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide,

[0155]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide,

[0156] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-nitrobenzamide,

[0157] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-aminobenzamide,

[0158] N-[5-(2-cyclohexylacetamido)-2-methylphenyl]-4-acetoxybenzamide,

[0159]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide,

[0160]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0161]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide and

[0162]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-acetoxybenzamide areexcluded.

[0163] A further preferred novel compound of the invention is an amidederivative of the Formula I wherein R¹ is hydroxy, methoxy, ethoxy,isopropoxy, carboxy, methoxycarbonyl, nitro, cyano, acetyl, acetoxy,methyl, ethyl, propyl, fluoro, chloro or trifluoromethyl;

[0164] m is 1, 2 or 3;

[0165] p is 0;

[0166] R³ is methyl;

[0167] q is 1,2, 3 or 4; and

[0168] R⁴ is cyclohexyl;

[0169] or a pharmaceutically-acceptable salt thereof;

[0170] except thatN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]4-hydroxybenzamide,

[0171]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetoxybenzamide,

[0172]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,

[0173]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide,

[0174]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide,

[0175] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-nitrobenzamide,

[0176] N-[5-(2-cyclohexylacetamido)-2-methylphenyl]-4-acetoxybenzamide,

[0177]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide,

[0178]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide and

[0179]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide areexcluded.

[0180] A further more preferred novel compound of the invention is anamide derivative of the Formula I wherein R¹ is hydroxy, methoxy,carboxy or acetoxy;

[0181] m is 1 or 2;

[0182] p is 0;

[0183] R³ is methyl;

[0184] q is 2, 3, or 4; and

[0185] R⁴ is cyclohexyl;

[0186] or a pharmaceutically-acceptable salt thereof;

[0187] except thatN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,

[0188]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetoxybenzamide,

[0189]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,

[0190]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide

[0191]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide and

[0192]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide areexcluded.

[0193] Particular compounds for use in the present invention are:

[0194]N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide;

[0195] N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-hydroxybenzamide;

[0196]N-[5-(5-cyclohexylvalerylamino)-2-methylphenyl]-4-hydroxybenzamide;

[0197]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]4-hydroxybenzamide;

[0198]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide;

[0199] N-(5-benzamido-2-methylphenyl)-4-hydroxybenzamide;

[0200]N-[5-(2-(3,4-dichlorophenyl)acetamido)-2-methylphenyl]4-hydroxybenzamide;

[0201] N-[5-(3,5-dimethoxybenzamido)-2-methylphenyl]-4-hydroxybenzamide;

[0202]N-[5-(2-fluoro-6-chlorobenzamido)-2-methylphenyl]4-hydroxybenzamide;

[0203]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide;

[0204] N-[5-(4-phenylbenzamido)-2-methylphenyl]-4-hydroxybenzamide;

[0205]N-[5-(2-(4-nitrophenyl)acetamido)-2-methylphenyl]-4-hydroxybenzamide,

[0206] N-[5-(2-cyclohexylpropionamido)-2-methylphenyl]4-acetylbenzamide;

[0207]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide;

[0208]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]4-methoxybenzamide;

[0209]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxy-3-methoxybenzamide;

[0210]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3,4-dimethoxybenzamide;

[0211]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxybenzamide;

[0212]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide; and

[0213]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-acetamidobenzamide;

[0214] and pharmaceutically-acceptable salts thereof.

[0215] Particular novel compounds of the present invention are:

[0216]N-[5-(3-benzyloxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide;

[0217] N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-acetoxybenzamide;

[0218] N-(5-benzamido-2-methylphenyl)-3,4-dimethoxybenzamide;

[0219] N-[5-(4-cyanobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide;

[0220] N-[5-(3-hydroxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide;

[0221]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-butoxybenzamide;

[0222]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3,4,5-trimethoxybenzamide;and

[0223]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-carboxybenzamide;

[0224] and pharmaceutically-acceptable salts thereof.

[0225] A further particular novel compound of the present invention is:N-[2-methyl-5-(3-trifluoromethylbenzamido)phenyl]-3,4-dimethoxybenzamide,and pharmaceutically-acceptable salts thereof.

[0226] In a further aspect of the present invention there is provided agroup of novel compounds of the Formula I wherein R⁴ is phenyl whichbears a basic substituent located at the 3- and/or 4-positions. Thisgroup of compounds possesses improved TNFα inhibitory potency in one orboth of the PBMC and Human Whole Blood tests described hereinafter.

[0227] A particular group of novel compounds according to this aspect ofthe invention is an amide derivative of the Formula I

[0228] wherein R¹ is hydroxy, C₁₋₆alkoxy, carboxy, C₁₋₆-alkoxycarbonyl,nitro, cyano, C₁₋₆alkanoylamino, C₁₋₆alkanoyl, C₁₋₆alkyl, halo ortrifluoromethyl;

[0229] m is 0-3 and when m is 2 or 3 each R¹ group is the same ordifferent;

[0230] p is 0;

[0231] R³ is methyl;

[0232] q is 0; and

[0233] R⁴ is phenyl which is substituted with 1 or 2 substituentsselected from amino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino,aminoC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl andheterocyclylC₁₋₆alkyl, and when there is 1 substituent it is located atthe 3-position and when there are 2 substituents, which may be the sameor different, they are located at the 3- and 4-positions;

[0234] or a pharmaceutically-acceptable salt thereof;

[0235] except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide isexcluded.

[0236] A preferred group of novel compounds according to this aspect ofthe invention is an amide derivative of the Formula I

[0237] wherein R¹ is hydroxy, methoxy, ethoxy, propoxy, isopropoxy,butoxy, carboxy, methoxycarbonyl, nitro, cyano, acetamido, acetyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro,bromo or trifluoromethyl;

[0238] m is 0-3 and when m is 2 or 3 each R¹ group is the same ordifferent;

[0239] p is 0;

[0240] R³ is methyl;

[0241] q is 0; and

[0242] R⁴ is phenyl which is substituted at the 3- or 4-position with asubstituent selected from amino, methylamino, dimethylamino,aminomethyl, pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl;

[0243] or a pharmaceutically-acceptable salt thereof;

[0244] except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide isexcluded.

[0245] A more preferred group of novel compounds according to thisaspect of the invention is an amide derivative of the Formula I

[0246] wherein (R¹)_(m) is 3,4-dimethoxy or 3,4,5-trimethoxy;

[0247] p is 0;

[0248] R³ is methyl;

[0249] q is 0; and

[0250] R⁴ is phenyl which is substituted at the 3-position with asubstituent selected from dimethylamino, morpholino, morpholinomethyl,piperazin-1-ylmethyl and 4-methylpiperazin-1-ylmethyl;

[0251] or a pharmaceutically-acceptable salt thereof.

[0252] A particular novel compound of this aspect of the presentinvention is:N-[2-methyl-5-(3-morpholinobenzamido)phenyl)-3.4,5-trimethoxybenzamide,and pharmaceutically-acceptable salts thereof.

[0253] In a further aspect of the present invention there is provided agroup of novel compounds of the Formula I wherein R¹ is a basicsubstituent located at the 3- and/or 4-positions. This group ofcompounds possesses improved TNFα inhibitory potency in one or both ofthe PBMC and Human Whole Blood tests described hereinafter.

[0254] A particular group of novel compounds according to this aspect ofthe invention is an amide derivative of the Formula I wherein R¹ isamino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino, aminoC₁₋₆alkyl, heteroaryl,heteroarylC₁₋₆alkyl, heterocyclyl or heterocyclylC₁₋₆alkyl;

[0255] m is 1 with the R¹ group located at the 3-position or m is 2 withthe R¹ groups, which may be the same or different, located at the 3- and4-positions;

[0256] p is 0;

[0257] R³ is methyl;

[0258] q is 0; and

[0259] R⁴ is phenyl which is optionally substituted with 1 or 2substituents, which may be the same or different, selected from hydroxy,C₁₋₆alkoxy, carboxy, C₁₋₆alkoxycarbonyl, cyano, C₁₋₆alkyl, halo andtrifluoromethyl;

[0260] or a pharmaceutically-acceptable salt thereof.

[0261] A preferred group of novel compounds according to this aspect ofthe invention is an amide derivative of the Formula I

[0262] wherein R¹ is amino, methylamino, dimethylamino, aminomethyl,pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl or 4-methylhomopiperazin-1-ylmethyl;

[0263] m is 1 with the R¹ group located at the 3- or 4-position;

[0264] p is 0;

[0265] R³ is methyl;

[0266] q is 0; and

[0267] R⁴ is phenyl which is optionally substituted with 1 or 2substituents, which may be the same or different, selected from hydroxy,methoxy, ethoxy, carboxy, methoxycarbonyl, cyano, methyl, fluoro, chloroand trifluoromethyl;

[0268] or a pharmaceutically-acceptable salt thereof.

[0269] A more preferred group of novel compounds according to thisaspect of the invention is an amide derivative of the Formula I

[0270] wherein R¹ is morpholino, morpholinomethyl, piperazin-1-ylmethylor 4-methylpiperazin-1-ylmethyl;

[0271] m is 1 with the R¹ group located at the 3-position;

[0272] p is 0;

[0273] R³ is methyl;

[0274] q is 0; and

[0275] R⁴ is phenyl which is optionally substituted with 1 or 2substituents, which may be the same or different, selected from methoxy,ethoxy, cyano, fluoro, chloro and trifluoromethyl;

[0276] or a pharmaceutically-acceptable salt thereof.

[0277] Particular novel compounds of this aspect of the presentinvention are:

[0278] N-(5-benzamido-2-methylphenyl)-3-(piperazin-1-yl)methylbenzamide,

[0279]N-(5-benzamido-2-methylphenyl)-3-(4-methylpiperazin-1-yl)methylbenzamide,

[0280]N-[2-methyl-5-(3-trifluoromethylbenzamido)phenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide,

[0281]N-[5-(3-chlorobenzamido)-2-methylphenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide,

[0282]N-[5-(2-methoxybenzamido)-2-methylphenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide

[0283] andN-[5-(3-ethoxybenzamido)-2-methylphenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide;

[0284] and pharmaceutically-acceptable salts thereof.

[0285] In yet another aspect of the present invention there is provideda group of novel compounds of the Formula I wherein (R¹)_(m) representsa basic substituent located at the 3- and/or 4-positions and R⁴ isphenyl which also bears a basic substituent located at the 3- and/or4-positions. This group of compounds possesses improved TNFα inhibitorypotency in one or both of the PBMC and Human Whole Blood tests describedhereinafter.

[0286] A particular group of novel compounds according to this aspect ofthe invention is an amide derivative of the Formula I

[0287] wherein R¹ is amino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino,aminoC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl orheterocyclylC₁₋₆alkyl;

[0288] m is 1 with the R¹ group located at the 3-position or m is 2 withthe R¹ groups, which may be the same or different, located at the 3- and4-positions;

[0289] p is 0;

[0290] R³ is methyl;

[0291] q is 0; and

[0292] R⁴ is phenyl which is substituted with 1 or 2 substituentsselected from amino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino,aminoC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl andheterocyclylC₁₋₄alkyl, and when there is 1 substituent it is located atthe 3-position and when there are 2 substituents, which may be the sameor different, they are located at the 3- and 4-positions;

[0293] or a pharmaceutically-acceptable salt thereof.

[0294] A preferred group of novel compounds according to this aspect ofthe invention is an amide derivative of the Formula I

[0295] wherein R¹ is amino, methylamino, dimethylamino, aminomethyl,pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl or 4-methylhomopiperazin-1-ylmethyl;

[0296] m is 1 with the R¹ group located at the 3- or 4-position;

[0297] p is 0;

[0298] R³ is methyl;

[0299] q is 0; and

[0300] R⁴ is phenyl which is substituted at the 3- or 4-position with asubstituent selected from amino, methylamino, dimethylamino,aminomethyl, pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl;

[0301] or a pharmaceutically-acceptable salt thereof.

[0302] A more preferred group of novel compounds according to thisaspect of the invention is an amide derivative of the Formula I

[0303] wherein R¹ is morpholino, morpholinomethyl, piperazin-1-ylmethylor 4-methylpiperazin-1-ylmethyl;

[0304] m is 1 with the R¹ group located at the 3-position;

[0305] p is 0;

[0306] R³ is methyl;

[0307] q is 0; and

[0308] R⁴ is phenyl which is substituted at the 3-position with asubstituent selected from dimethylamino morpholino, morpholinomethyl,piperazin-1-ylmethyl and 4-methylpiperazin-1-ylmethyl;

[0309] or a pharmaceutically-acceptable salt thereof.

[0310] Particular novel compounds of this aspect of the presentinvention are:

[0311]N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-morpholinobenzamide and

[0312]N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide;

[0313] and pharmaceutically-acceptable salts thereof

[0314] A suitable pharmaceutically-acceptable salt of a compound of theFormula I is, for example, an acid-addition salt of a compound of theFormula I which is sufficiently basic, for example an acid-addition saltwith an inorganic or organic acid such as hydrochloric, hydrobromic,sulphuric, trifluoroacetic, citric or maleic acid; or, for example asalt of a compound of the Formula I which is sufficiently acidic, forexample an alkali or alkaline earth metal salt such as a calcium ormagnesium salt, or an ammonium salt, or a salt with an organic base suchas methylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

[0315] Various forms of prodrugs are known in the art. For examples ofsuch prodrug derivatives, see:

[0316] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)and Methods in Enzymology, Vol. 42 p. 309-396, edited by K. Widder, etal. (Academic Press, 1985);

[0317] b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard. Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

[0318] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0319] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,285 (1988); and

[0320] e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

[0321] Examples of such pro-drugs may be used to form in vivo cleavableesters of a compound of the Formula I. An in vivo cleavable ester of acompound of the Formula I containing a carboxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethylesters, for example methoxymethyl; C₁₋₆alkanoyloxymethyl esters, forexample pivaloyloxymethyl; phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters, for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and C₁₋₆alkoxycarbonyloxyethylesters, for example 1-methoxycarbonyloxyethyl; and may be formed at anycarboxy group in the compounds of this invention.

[0322] In order to use a compound of the Formula I, or apharmaceutically-acceptable salt or in vivo cleavable ester thereof, forthe therapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

[0323] According to this aspect of the invention there is provided apharmaceutical composition which comprises an amide derivative of theFormula I, or a pharmaceutically-acceptable salt or in vivo cleavableester thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

[0324] The compositions of the invention may be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

[0325] The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

[0326] Suitable pharmaceutically-acceptable excipients for a tabletformulation include, for example, inert diluents such as lactose, sodiumcarbonate, calcium phosphate or calcium carbonate, granulating anddisintegrating agents such as corn starch or algenic acid; bindingagents such as starch; lubricating agents such as magnesium stearate,stearic acid or talc; preservative agents such as ethyl or propylp-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tabletformulations may be uncoated or coated either to modify theirdisintegration and the subsequent absorption of the active ingredientwithin the gastrointestinal tract, or to improve their stability and/orappearance, in either case, using conventional coating agents andprocedures well known in the art.

[0327] Compositions for oral use may be in the form of hard gelatincapsules in which the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules in which the active ingredient is mixed withwater or an oil such as peanut oil, liquid paraffin, or olive oil.

[0328] Aqueous suspensions generally contain the active ingredient infinely powdered form together with one or more suspending agents, suchas sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

[0329] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil (such as arachis oil, olive oil, sesameoil or coconut oil) or in a mineral oil (such as liquid paraffin). Theoily suspensions may also contain a thickening agent such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

[0330] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

[0331] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, such as olive oil or arachis oil, or a mineral oil, such as forexample liquid paraffin or a mixture of any of these. Suitableemulsifying agents may be, for example, naturally-occurring gums such asgum acacia or gum tragacanth, naturally-occurring phosphatides such assoya bean, lecithin, an esters or partial esters derived from fattyacids and hexitol anhydrides (for example sorbitan monooleate) andcondensation products of the said partial esters with ethylene oxidesuch as polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening, flavouring and preservative agents.

[0332] Syrups and elixirs may be formulated with sweetening agents suchas glycerol, propylene glycol, sorbitol, aspartame or sucrose, and mayalso contain a demulcent, preservative, flavouring and/or colouringagent.

[0333] The pharmaceutical compositions may also be in the form of asterile injectable aqueous or oily suspension, which may be formulatedaccording to known procedures using one or more of the appropriatedispersing or wetting agents and suspending agents, which have beenmentioned above. A sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example a solution in 1,3-butanediol.

[0334] Suppository formulations may be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Suitable excipientsinclude, for example, cocoa butter and polyethylene glycols.

[0335] Topical formulations, such as creams, ointments, gels and aqueousor oily solutions or suspensions, may generally be obtained byformulating an active ingredient with a conventional, topicallyacceptable, vehicle or diluent using conventional procedures well knownin the art.

[0336] Compositions for administration by insufflation may be in theform of a finely divided powder containing particles of average diameterof, for example, 30 μm or much less, the powder itself comprising eitheractive ingredient alone or diluted with one or more physiologicallyacceptable carriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

[0337] Compositions for administration by inhalation may be in the formof a conventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

[0338] For further information on Formulation the reader is referred toChapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (CorwinHansch; Chairman of Editorial Board), Pergamon Press 1990.

[0339] The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

[0340] The size of the dose for therapeutic or prophylactic purposes ofa compound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

[0341] In using a compound of the Formula I for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.5 mg to 75 mg per kg body weight,preferably 0.5 mg to 40 mg per kg body weight, is received, given ifrequired in divided doses. In general lower doses will be administeredwhen a parenteral route is employed. Thus, for example, for intravenousadministration, a dose in the range, for example, 0.5 mg to 30 mg per kgbody weight will generally be used. Similarly, for administration byinhalation, a dose in the range, for example, 0.5 mg to 25 mg per kgbody weight will be used. Oral administration is however preferred,particularly in tablet form. Typically, unit dosage forms will containabout 1 mg to 500 mg of a compound of this invention.

[0342] The compounds of this invention may be used in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of cytokines, in particular TNF andIL-1. For example, the compounds of the Formula I could be used incombination with drugs and therapies used in the treatment of rheumatoidarthritis, asthma, irritable bowel disease, multiple sclerosis. AIDS,septic shock, ischaemic heart disease, psoriasis and the other diseasestates mentioned earlier in this specification.

[0343] For example, by virtue of their ability to inhibit cytokines, thecompounds of the Formula I are of value in the treatment of certaininflammatory and non-inflammatory diseases which are currently treatedwith a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug(NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid,ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of acompound of the Formula I with a NSAID can result in a reduction of thequantity of the latter agent needed to produce a therapeutic effect.Thereby the likelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises a compound of the Formula I, or apharmaceutically-acceptable salt or in vivo cleavable ester thereof, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent, and a pharmaceutically-acceptable diluent orcarrier.

[0344] The compounds of the invention may also be used withanti-inflammatory agents such as an inhibitor of the enzyme5-lipoxygenase (such as those disclosed in European Patent ApplicationsNos. 0351194, 0375368, 0375404, 0375452, 0375457, 0381375, 0385662,0385663, 0385679, 0385680).

[0345] The compounds of the Formula I may also be used in the treatmentof conditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

[0346] The compounds of the present invention may also be administeredin degradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

[0347] The compounds of the Formula I may be be used in the treatment ofasthma in combination with antiasthmatic agents such as bronchodilatorsand leukotriene antagonists.

[0348] If formulated as a fixed dose such combination products employthe compounds of this invention within the dosage range described hereinand the other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

[0349] Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofcytokines. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

[0350] An amide derivative of the Formula I, or apharmaceutically-acceptable salt or in vivo cleavable ester thereof, maybe prepared by any process known to be applicable to the preparation ofchemically-related compounds. Suitable processes are illustrated by, forexample, those used in J. Med. Chem., 1996, 39, 3343-3356. Suchprocesses, when used to prepare a novel amide derivative of the FormulaI are provided as a further feature of the invention and are illustratedby the following representative process variants in which, unlessotherwise stated. R¹, R², R³, R⁴, m, p and q have any of the meaningsdefined hereinbefore. Necessary starting materials may be obtained bystandard procedures of organic chemistry. The preparation of suchstarting materials is described in conjunction with the followingrepresentative process variants and within the accompanying Examples.Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

[0351] (a) A compound of the Formula I, or a pharmaceutically-acceptablesalt or in vivo cleavable ester thereof, may be prepared by reacting acompound of the Formula III

[0352] with a compound of the Formula IV

[0353] or an activated derivative thereof, under standard amide bondforming conditions, wherein variable groups are as hereinbefore definedand wherein any functional group is protected, if necessary, and:

[0354] i. removing any protecting groups;

[0355] ii. optionally forming a pharmaceutically-acceptable salt or invivo cleavable ester.

[0356] A suitable activated derivative of an acid of the Formula IV is,for example, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride: a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate,an active ester, for example an ester formed by the reaction of the acidand a phenol such as pentafluorophenol, an ester such aspentafluorophenyl trifluoroacetate or an alcohol such asN-hydroxybenzotriazole; an acyl azide, for example an azide formed bythe reaction of the acid and an azide such as diphenylphosphoryl azide;an acyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asdicyclohexylcarbodiimide.

[0357] The reaction is preferably carried out in the presence of asuitable base such as, for example, an alkali or alkaline earth metalcarbonate, alkoxide, hydroxide or hydride, for example sodium carbonate,potassium carbonate, sodium ethoxide, potassium butoxide, sodiumhydroxide, potassium hydroxide, sodium hydride or potassium hydride, oran organometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, −78° to 150° C. conveniently at or near ambient temperature.

[0358] Typically a carbodiimide coupling reagent is used in the presenceof an organic solvent (preferably an anhydrous polar aprotic organicsolvent) at a non-extreme temperature, for example in the region −10 to40° C., typically at ambient temperature of about 20° C.

[0359] Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

[0360] Specific examples of protecting groups are given below for thesake of convenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned is of course within the scope of the invention.

[0361] A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).

[0362] Examples of carboxy protecting groups include straight orbranched chain C₁₋₁₂alkyl groups (for example isopropyl, tert-butyl);lower alkoxy lower alkyl groups (for example methoxymethyl,ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkylgroups, (for example acetoxymethyl, propionyloxymethyl,butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy loweralkyl groups (for example 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for example benzyl,p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl andphthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyland tert-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups(for example trimethylsilylethyl); and C₂₋₆alkenyl groups (for exampleallyl and vinylethyl).

[0363] Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed hydrolysis.

[0364] Examples of hydroxy protecting groups include lower alkyl groups(for example tert-butyl) lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl) andaryl lower alkyl (for example benzyl) groups.

[0365] Examples of amino protecting groups include formyl, aralkylgroups (for example benzyl and substituted benzyl, p-methoxybenzyl,nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-p-anisylmethyl and furylmethyl groups: lower alkoxycarbonyl (forexample tert-butoxycarbonyl): lower alkenyloxycarbonyl (for exampleallyloxycarbonyl): aryl lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example methylidene);benzylidene and substituted benzylidene groups.

[0366] Methods appropriate for removal of hydroxy and amino protectinggroups include, for example, acid-, base-, metal- orenzymically-catalysed hydrolysis for groups such asp-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl andphotolytically for groups such as o-nitrobenzyloxycarbonyl.

[0367] The reader is referred to Advanced Organic Chemistry, 4thEdition, by Jerry March, published by John Wiley & Sons 1992, forgeneral guidance on reaction conditions and reagents. The reader isreferred to Protective Groups in Organic Synthesis, 2nd Edition, byGreen et al., published by John Wiley & Sons for general guidance onprotecting groups.

[0368] The compound of Formula III may be prepared by reduction of thecorresponding nitro compound of Formula V.

[0369] Typical reaction conditions include the use of ammonium form atein the presence of a catalyst (for example palladium-on-carbon) in thepresence of an organic solvent (preferably a polar protic solvent),preferably with heating, for example to about 60° C. Any functionalgroups are protected and deprotected as necessary.

[0370] The compound of Formula V may be prepared by reaction of acompound of Formula VI, or an activated derivative thereof as definedhereinbefore,

[0371] with a compound of Formula VII under suitable amide bond formingconditions

[0372] Typical conditions include activating the carboxy group of thecompound of Formula VI for example by treatment with a halo reagent (forexample oxalyl chloride) to form an acyl halide in an organic solvent atambient temperature, then reacting the activated compound with thecompound of Formula VII. Any functional groups are protected anddeprotected as necessary.

[0373] (b) A compound of the Formula I, or a pharmaceutically-acceptablesalt or in vivo cleavable ester thereof, may be prepared by reacting anacid of the Formula VI

[0374] or an activated derivative thereof as defined hereinbefore, withan aniline of the Formula VIII

[0375] under standard amide bond forming conditions, wherein variablegroups are as hereinbefore defined and wherein any functional group isprotected, if necessary, and:

[0376] i. removing any protecting groups;

[0377] ii. optionally forming a pharmaceutically-acceptable salt or invivo cleavable ester.

[0378] The aniline of Formula VIII may be prepared by reduction of thecorresponding nitro compound using convention procedures as definedhereinbefore or as illustrated in the Examples.

[0379] (c) A compound of the Formula I wherein R¹ or a substituent on R⁴is heterocyclylC₁₋₆alkyl may be prepared by the reaction of a compoundof the Formula I wherein R¹ or a substituent on R⁴ is a group of theformula —C₁₋₆alkyl-Z wherein Z is a displaceable group with aheterocyclyl compound.

[0380] A suitable displaceable group Z is, for example, a halogeno groupsuch as fluoro, chloro or bromo a C₁₋₆alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

[0381] The reaction is conveniently carried out in the presence of asuitable base as defined hereinbefore and in the presence of a suitableinert diluent or carrier as defined hereinbefore.

[0382] (d) A compound of the Formula I wherein R¹, R² or a substituenton R⁴ is carboxy may be prepared by the cleavage of a compound of theFormula I wherein R¹, R² or a substituent on R⁴ is C₁₋₆alkoxycarbonyl.

[0383] The cleavage reaction may conveniently be carried out by any ofthe many procedures known in the art for such a transformation. Thereaction may be carried out, for example, by hydrolysis under acidic orbasic conditions. A suitable base is, for example, an alkali metal,alkaline earth metal or ammonium carbonate or hydroxide, for examplesodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide or ammonium hydroxide. The reaction is preferably carried outin the presence of water and a suitable solvent or diluent such asmethanol or ethanol. The reaction is conveniently carried out at atemperature in the range 10 to 150° C., preferably at or near ambienttemperature.

[0384] (e) A compound of the Formula I wherein R¹, R² or a substituenton R⁴ is hydroxy may be prepared by cleavage of a compound of theFormula I wherein R¹, R² or a substituent on R⁴ is benzyloxy orsubstituted benzyloxy.

[0385] Typical reaction conditions include the hydrogenolysis of abenzyloxy group in the presence of a suitable catalyst such aspalladium-on-carbon.

[0386] (f) A compound of the Formula I wherein R¹, R² or a substituenton R⁴ is amino may be prepared by the reduction of a compound of theFormula I wherein R¹, R² or a substituent on R⁴ is nitro.

[0387] Typical reaction conditions include the use of hydrogen or ofammonium formate in the presence of a suitable catalyst such aspalladium-on-carbon.

[0388] (g) A compound of the Formula I wherein R¹ R² or a substituent onR⁴ is C₁₋₆alkanoylamino may be prepared by the acylation of a compoundof the Formula I wherein R¹, R² or a substituent on R⁴ is amino.

[0389] A suitable acylating agent is, for example, any agent known inthe art for the acylation of amino to acylamino, for example an acylhalide, for example a C₁₋₆alkanoyl chloride or bromide, conveniently inthe presence of a suitable base, as defined hereinbefore, an alkanoicacid anhydride or mixed anhydride, for example a C₁₋₆alkanoic acidanhydride such as acetic anhydride or the mixed anhydride formed by thereaction of an alkanoic acid and a C₁₋₆alkoxycarbonyl halide, forexample a C₁₋₆alkoxycarbonyl chloride, in the presence of a suitablebase as defined hereinbefore. In general the acylation is carried out ina suitable inert solvent or diluent as defined hereinbefore and at atemperature, in the range, for example, −30 to 120° C., conveniently ator near ambient temperature.

[0390] The following biological assays and Examples serve to illustratethe present invention.

[0391] Biological Assays

[0392] The following assays can be used to measure the p38kinase-inhibitory, the TNF-inhibitory and anti-arthritic effects of thecompounds of the present invention:

[0393] In vitro Enzyme Assay

[0394] The ability of compounds of the invention to inhibit the enzymep38 kinase was assessed. Activity of particular test compounds againsteach of the p38α and p38β isoforms of the enzyme was determined.

[0395] Human recombinant MKK6 (GenBank Accesion Number G1209672) wasisolated from Image clone 45578 (Genomics, 1996, 33, 151) and utilisedto produce protein in the form of a GST fusion protein in a pGEX vectorusing analogous procedures to those disclosed by J. Han et al., Journalof Biological Chemistry, 1996, 271, 2886-2891, p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM1416) and human foetal brain cDNA [synthesised frommRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38β genes using analogous proceduresto those described by J. Han et al., Biochimica et Biophysica Acta,1995, 1265, 224-227 and Y. Jiang et al. Journal of Biological Chemistry1996, 271, 17920-17926.

[0396] Both p38 protein isoforms were expressed in e coli in PETvectors. Human recombinant p38α and p38β isoforms were produced as 5′c-myc, 6His tagged proteins. Both MKK6 and the p38 proteins werepurified using standard protocols: the GST MKK6 was purified using aglutathione sepharose column and the p38 proteins were purified usingnickel chelate columns.

[0397] The p38 enzymes were activated prior to use by incubation withMKK6 for 3 hours at 30° C. The unactivated coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38. Theactivation incubate comprised p38α (10 μl of 10 mg/ml) or p38β (10 μl of5 mg/ml) together with MKK6 (1 μl of 1 mg/ml), ‘Kinase buffer’ [100 μl;pH 7.4 buffer comprising Tris (50 mM), EGTA (0. 1 mM), sodiumorthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (30 μl of50 mM Mg(OCOCH₃)₂ and 0.5 mM ATP). This produced enough activated p38enzyme for 3 Microtiter plates.

[0398] Test compounds were solubilised in DMSO and 10 μl of a 1:10diluted sample in ‘Kinase Buffer’ was added to a well in a Microtiterplate. For single dose testing, the compounds were tested at 10 μM.‘Kinase Assay Mix’ [30 μl; comprising Myelin Basic Protein (Gibco BRLcat. no. 1322B-010; 1 ml of a 3.33 mg/ml solution in water), activatedp38 enzyme (50 μl) and ‘Kinase Buffer’ (2 ml)] was then added followedby ‘Labelled ATP’ [10 μl; comprising 50 μM ATP, 0.1 μCi ³³P ATP(Amersham International cat. no. BF1000) and 50 mM Mg(OCOCH₃)₂]. Theplates were incubated at room temperature with gentle agitation. Platescontaining p38α were incubated for 90 min and plates containing p38βwere incubated for 45 min. Incubation was stopped by the addition of 50μl of 20% trichloroacetic acid (TCA). The precipitated protein wasphosphorylated by p38 kinase and test compounds were assessed for theirability to inhibit this phosphorylation. The plates were filtered usinga Canberra Packard Unifilter and washed with 2% TCA, dried overnight andcounted on a Top Count scintillation counter.

[0399] Test compounds were tested initially at a single dose and activecompounds were retested to allow IC₅₀ values to be determined.

[0400] In vitro Cell-Based Assays

[0401] (i) PBMC

[0402] The ability of compounds of this invention to inhibit TNFαproduction was assessed by using human peripheral blood mononuclearcells which synthesise and secrete TNFα when stimulated withlipopolysaccharide.

[0403] Peripheral blood mononuclear cells (PBMC) were isolated fromheparinised (10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed). Mononuclear cells were resuspended in culturemedium [RPMI 1640 medium (Gibco) supplemented with 50 units/mlpenicillin, 50 μg/ml streptomycin, 2 mM glutamine and 1%heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 50 mM, diluted 1:100 inculture medium and subsequently serial dilutions were made in culturemedium containing 1% DMSO. PBMCs (2.4×10⁵ cells in 160 μl culturemedium) were incubated with 20 μl of varying concentrations of testcompound (triplicate cultures) or 20 μl culture medium containing 1%DMSO (control wells) for 30 minutes at 37° C. in a humidified (5%CO₂/95%air) incubator (Falcon 3072; 96 well flat-bottom tissue culture plates).20 μl lipopolysaccharide [LPS E.Coli 0111:B4 (Sigma L-4130), finalconcentration 10 μg/ml] solubilised in culture medium was added toappropriate 30 wells. 20 μl culture medium was added to “medium alone”control wells. Six “LPS alone” and four “medium alone” controls wereincluded on each 96 well plate. Varying concentrations of a known TNFαinhibitor were included in each test, i.e. an inhibitor of the PDE TypeIV enzyme (for example see Semmler, J. Wachtel. H and Endres. S., Int.J. Immunopharmac. (1993), 15(3), 409-413) or an inhibitor of proTNFαconvertase (for example, see McGeehan, G. M. et al. Nature (1994) 370,558-561). Plates were incubated for 7 hours at 37° C. (humidifiedincubator) after which 100 μl of the supernatant was removed from eachwell and stored at −70° C. (96 well round-bottom plates; Corning 25850).TNFα levels were determined in each sample using a human TNFα ELISA (seeWO92/10190 and Current Protocols in Molecular Biology, vol 2 byFrederick M. Ausbel et al., John Wiley and Sons Inc.).${\% \quad {inhibition}} = {\frac{\begin{matrix}{\left( {{{LPS}\quad {alone}\quad {control}} - {{medium}\quad {alone}\quad {control}}} \right) -} \\\left( {{{test}\quad {concentration}} - {{medium}\quad {alone}\quad {control}}} \right)\end{matrix}}{\left( {{{LPS}\quad {alone}\quad {control}} - {{medium}\quad {alone}\quad {control}}} \right)} \times 100}$

[0404] (ii) Human Whole Blood

[0405] The ability of the compounds of this invention to inhibit TNFαproduction was also assessed in a human whole blood assay. Human wholeblood secretes TNFα when stimulated with LPS. This property of bloodforms the basis of an assay which is used as a secondary test forcompounds which profile as active in the PBMC test.

[0406] Heparinised (10 units/ml) human blood was obtained fromvolunteers. 160 μl whole blood were added to 96 well round-bottom plates(Corning 25850). Compounds were solubilised and serially diluted in RPMI1640 medium (Gibco) supplemented with 50 units/ml penicillin, 50 μg/mlstreptomycin and 2 mM glutamine, as detailed above. 20 μl of each testconcentration was added to appropriate wells (triplicate cultures). 20μl of RPMI 1640 medium supplemented with antibiotics and glutamine wasadded to control wells. Plates were incubated for 30 minutes at 37° C.(humidified incubator), prior to addition of 20 μl LPS (finalconcentration 10 μg/ml). RPMI 1640 medium was added to control wells.Six “LPS alone” and four “medium alone” controls were included on eachplate. A known TNFα synthesis/secretion inhibitor was included in eachtest. Plates were incubated for 6 hours at 37° C. (humidifiedincubator). Plates were centrifuged (2000 rpm for 10 minutes) and 100 μlplasma removed and stored at −70° C. (Corning 25850 plates). TNFα levelswere measured by ELISA (see WO92/10190 and Current Protocols inMolecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley andSons Inc.). The paired antibodies that were used in the ELIZA wereobtained from R&D Systems (catalogue nos. MAB610 anti-human TNFα coatingantibody, BAF210 biotinylated anti-human TNFα detect antibody).

[0407] Ex vivo/In vivo Assessment

[0408] The ability of the compounds of this invention as ex vivo TNFαinhibitors were assessed in the rat or mouse. Briefly, groups of maleWistar Alderley Park (AP) rats (180-210 g) were dosed with compound (6rats) or drug vehicle (10 rats) by the appropriate route, for exampleperoral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c.). Ninetyminutes later rats were sacrificed using a rising concentration of CO₂and bled out via the posterior vena cavae into 5 Units of sodiumheparin/ml blood. Blood samples were immediately placed on ice andcentrifuged at 2000 rpm for 10 min at 4° C. and the harvested plasmasfrozen at −20° C. for subsequent assay of their effect on TNFαproduction by LPS-stimulated human blood. The rat plasma samples werethawed and 1751 μl of each sample was added to a set format pattern in a96 well round bottom plate (Coming 25850). 50 μl of heparinized humanblood was then added to each well, mixed and the plate was incubated for30 min at 37° C. (humidified incubator). LPS (25 μl; final concentration10 μg/ml) was added to the wells and incubation continued for a further5.5 hours. Control wells were incubated with 25 μl of medium alone.Plates were then centrifuged for 10 min at 2000 rpm and 200 μl of thesupernatants were transferred to a 96 well plate and frozen at −20° C.for subsequent analysis of TNF concentration by ELISA.

[0409] Data analysis by dedicated software calculates for eachcompound/dose:${{Percent}\quad {inhibition}\quad {of}\quad {TNF}\quad \alpha} = \frac{\begin{matrix}{{{Mean}\quad {TNF}\quad \alpha \quad ({Controls})} -} \\{{Mean}\quad {TNF}\quad \alpha \quad ({Treated}) \times 100}\end{matrix}}{{Mean}\quad {TNF}\quad \alpha \quad ({Controls})}$

[0410] Alternatively, mice could be used instead of rats in the aboveprocedure.

[0411] Test as Anti-Arthritic Agent

[0412] Activity of a compound as an anti-arthritic agent was tested asfollows. Acid soluble native type 11 collagen was shown by Trentham etal. [1] to be arthritogenic in rats; it caused polyarthritis whenadministered in Freunds incomplete adjuvant. This is now known ascollagen-induced arthritis (CIA) and similar conditions can be inducedin mice and primates. Recent studies have shown that anti-TNF monoclonalantibodies [2] and TNF receptor-IgG fusion proteins [3] ameliorateestablished CIA indicating that TNF plays a key role in thepathophysiology of CIA. Moreover, the remarkable efficacy reported foranti-TNF monoclonal antibodies in recent rheumatoid arthritis clinicaltrials indicates that TNF plays a major role in this chronicinflammatory disease. Thus CIA in DBA/1 mice as described in references2 and 3 is a tertiary model which can be used to demonstrate theanti-arthritic activity of a compound. Also see reference 4.

[0413] 1. Trentham, D. E. et al., (1977) J. Exp. Med., 146 857.

[0414] 2. Williams, R. O. et al., (1992) Proc. Natl. Acad. Sci., 89,9784.

[0415] 3. Williams, R. O. et al., (1995) Immunology, 84, 433.

[0416] 4 Badger, M. B. et al., (1996) The Journal of Pharmacology andExperimental Therapeutics, 279, 1453-1461.

[0417] Although the pharmacological properties of the compounds of theFormula I vary with structural change as expected, in general a compoundof the Formula I gives over 30% inhibition of p38α and/or p38β atconcentrations up to 10 μM and over 30% inhibition in the PBMC test atconcentrations up to 50 μM. No physiologically unacceptable toxicity wasobserved at the effective dose for compounds tested of the presentinvention. By way of example:—

[0418]N-[5-(2-fluoro-6-chlorobenzamido-2-methylphenyl]-4-hydroxybenzamide[Example 9, Compound No. 12] has an IC₅₀ of approximately 1.7 μM againstp38α and an IC₅₀ of approximately 22 μM in the PBMC test;

[0419] N-[5-(3-aminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide[Example 13] has an IC₅₀ of approximately 0.7 μM against p38α and anIC₅₀ of approximately 7 μM in the PBMC test;

[0420]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide[Example 9, Compound No. 7] has an IC₅₀ of approximately 0.2 μM againstp38α and an IC₅₀ of approximately 7 μM in the PBMC test;

[0421]N-(5-benzamido-2-methylphenyl)-3-(4-methylpiperazin-1-yl)methylbenzamide,[Example 9, Compound No. 51] has an IC₅₀ of approximately 0.7 μM againstp38α and an IC₅₀ of approximately 3 μM in the PBMC test;

[0422]N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-morpholinobenzamide[Example 9, Compound No. 50] has an IC₅₀ of approximately 0.04 μMagainst p38α and an IC₅₀ of approximately 1.5 μM in the PBMC test;

[0423]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide hasan IC₅₀ of approximately 6 μM against p38α; and

[0424]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxybenzamide hasan IC₅₀ of approximately 0.4 μM against p38α and an IC₅₀ ofapproximately 7 μM in the PBMC test.

[0425] The invention will now be illustrated in the followingnon-limiting Examples in which, unless otherwise stated:—

[0426] (i) operations were carried out at ambient temperature, i.e. inthe range 17 to 25° C. and under an atmosphere of an inert gas such asargon unless otherwise stated;

[0427] (ii) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidsby filtration;

[0428] (iii) column chromatography (by the flash procedure) and mediumpressure liquid chromatography (MPLC) were performed on Merck Kieselgelsilica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phasesilica obtained from E. Merck, Darmstadt Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

[0429] (iv) yields are given for illustration only and are notnecessarily the maximum attainable;

[0430] (v) in general, the end-products of the Formula I havesatisfactory microanalyses and their structures were confirmed bynuclear magnetic resonance (NMR) and/or mass spectral techniques;fast-atom bombardment (FAB) mass spectral data were obtained using aPlatform spectrometer and, where appropriate, either positive ion dataor negative ion data were collected; NMR chemical shift values weremeasured on the delta scale [proton magnetic resonance spectra weredetermined using a Varian Gemini 2000 spectrometer operating at a fieldstrength of 300 MHz or a Bruker AM250 spectrometer operating at a fieldstrength of 250 MHz]; the following abbreviations have been used: s,singlet; d, doublet; t, triplet; m, multiplet; br, broad;

[0431] (vi) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatographic, HPLC, infra-red (IR)and/or NMR analysis;

[0432] (vii) melting points are uncorrected and were determined using aMettler SP62 automatic melting point apparatus or an oil-bath apparatus;melting points for the end-products of the Formula I were determinedafter crystallisation from a conventional organic solvent such asethanol, methanol, acetone, ether or hexane, alone or in admixture, and(viii) the following abbreviations have been used:—

[0433] DMF N,N-dimethylformamide

[0434] DMSO dimethylsulfoxide

[0435] MPLC medium pressure liquid chromatography

[0436] HPLC high pressure liquid chromatography

EXAMPLE 1

[0437] N-[5-(2-Bicyclo [2.2.11hept-2-ylacetylamino)-2-methylphenyl]-4-hydroxybenzamide

[0438] A solution of N-(5-amino-2-methylphenyl)-4-hydroxybenzamide (133mg) in dry DMF (0.5 ml) was added to 2-norbornanylacetic acid (77 mg)followed by a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (96 mg) in dry methylene chloride (3.0 ml). The reactionwas stirred at ambient temperature for 5 hours. The solvents wereremoved by evaporation and the residue taken up into ethyl acetate (4.0ml) and washed with water (3.0 ml). The aqueous layer was back extractedwith ethyl acetate (4.0 ml) and the combined ethyl acetate extracts wereevaporated to give 95 mg (53%) of the title product, shown to be 96%pure by HPLC.

[0439] The starting material was prepared as follows:

[0440] A) Oxalyl chloride (0.5 ml) was added slowly to a stirredsuspension of 4-acetoxybenzoic acid (1.09 g), dry methylene chloride (30ml) and DMF (one drop). The mixture was stirred for two hours at ambienttemperature. A solution of 2-methyl-5-nitroaniline (760 mg) and pyridine(2.0 ml) in dry methylene chloride was added over 15 minutes. Thereaction mixture was stirred for a further 2 hours, washed with 5%aqueous acetic acid (2×25 ml), water (20 ml) and 5% aqueous sodiumhydrogen carbonate solution. The organic extract was dried overmagnesium sulphate, filtered and evaporated to dryness. The residue wascrystallised from ethyl acetate (100 ml) to give 800 mg (53%) of4-acetoxy-N-(2-methyl-5-nitrophenyl)benzamide, melting point 207-208°C.;

[0441] NMR Spectrum: (DMSOd₆) 2.3 (s, 3H), 7.31 (d, 2H), 7.56 (d, 1H),8.02 (m, 3H), 8.47 (d, 1H), 10.12 (s, 1H); Mass Spectrum: M+H⁺ 315;Microanalysis: % Theory C 61.1, H 4.49, N 8.91 % Found C 61.0, H 4.3, N8.8%.

[0442] B) A stirred mixture of4-acetoxy-N-(2-methyl-5-nitrophenyl)benzamide (500 mg), ammonium formate(1.0 g) and 10% palladium on carbon (25 mg) in methanol (10 ml) washeated at 60° C. for 2 hours. The reaction mixture was cooled andfiltered through diatomaceous earth (Celite®). The filtrate wasevaporated to dryness and the residue triturated with water. The crudeproduct was filtered from the aqueous solution and crystallised frommethanol to give 140 mg (31% yield) ofN-(5-amino-2-methylphenyl)-4-hydroxybenzamide, Melting point 277-278°C.;

[0443] NMR Spectrum: (DMSOd₆) 2.03 (s, 3H), 4.85 (s, 2H), 6.39 (m, 1H),6.61 (d, 1H), 6.85 (m, 3H), 7.82 (d, 2H), 9.3 (s, 1H), 9.96 (s, 1H);Mass Spectrum: M+H⁺ 243; Microanalysis: C₁₄H₁₄N₂O₂ requires C, 69.4; H,5.8; N 11.6%; found C, 69.1; H, 5.8; N 11.5%.

EXAMPLE 2

[0444]N-{5-[2-(3,4-Dichlorophenyl)acetylamino]-2-methylphenyl}-4-hydroxybenzamide

[0445] The method of Example 11315 was repeated using3,4-dichlorophenylacetic acid (0.5 mmol). The reaction mixture wasevaporated and the residue taken up in ethyl acetate (4 ml), washed with1M hydrochloric acid (3.0 ml) and water (3.0 ml). The ethyl acetateextract was evaporated to give the desired product, 132 mg (68%), shownto be 92% pure by HPLC.

EXAMPLE 3

[0446]N-[5-(3-Dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide

[0447] N-(5-Amino-2-methylphenyl)-4-hydroxybenzamide (85 mg) was addedto a stirred solution of 3-dimethylaminobenzoic acid (89 mg) in dry DMF(0.5 ml) followed by a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (103 mg) indry methylene chloride (3 ml) and 4-dimethylaminopyridine (131 mg; 1.07mmol). The reaction was stirred at ambient temperature under argon for18 hours. The reaction mixture was purified by MPLC on silica eluting inturn with 50%, 60% and 70% ethyl acetate in isohexane to give 17 mg(11%) of the title product; NMR Spectrum: (DMSOd₆) 2.17 (s, 3H), 2.96(s, 6H), 6.80-6.95 (m, 3H), 7.15-7.35 (m, 4H), 7.58 (m, 1H), 7.79 (d,1H), 7.87 (d, 2H), 9.62 (s, 1H), 9.95 (s, 1H), 10.10 (s, 1H); MassSpectrum: M+H⁺ 390; Microanalysis: % Theory C 68.6, H 5.8, N 10.3 (0.2CH₂Cl₂), % Found C 68.1, H 5.7, N 10.9.

EXAMPLE 4

[0448] N-[5-(4-Cyanobenzamido)-2-methylphenyl]-4-hydroxybenzamide

[0449] A solution of N-(5-amino-2-methylphenyl)-4-hydroxybenzamide (121mg) in dry DMF (1.0 ml) was added to 4-cyanobenzoic acid (88 mg), andstirred. A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (115 mg) in methylene chloride (3.0 ml) was added and themixture stirred at ambient temperature overnight. The solvent was thenevaporated and the residue treated with 5% aqueous sodium hydrogencarbonate solution (3 ml) and extracted with ethyl acetate (3×5 ml). Theorganic layer was washed with water (3 ml) and filtered through a silicacolumn eluting with ethyl acetate (3×15 ml). The solvent was evaporatedand the residue crystallised from ethanol/water (1:1) to give the titleproduct (70 mg), m.p. 297-299° C.;

[0450] NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 6.88 (d, 2H), 7.23 (d, 1H),7.56 (m, 1H), 7.85 (m, 3H), 8.0 (d, 2H), 8.12 (d, 2H), 9.62 (s, 1H),10.02 (s, 1H), 10.45 (s, 1H); Mass Spectrum: M+H⁺ 372; Microanalysis: %Theory C 70.5, H 4.6, N 11.2, % Found C 70.5, H 4.4, N 10.8.

EXAMPLE 5

[0451] N-[5-(4-chlorobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0452] Triethylamine (0.12 ml) was added to a stirred mixture ofN-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (0.1 g),4-chlorobenzoyl chloride (0.067 ml), 4-dimethylaminopyridine (0.004 g)and methylene chloride (3 ml) and the mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was partitioned betweenmethylene chloride and 2N hydrochloric acid. The organic phase waswashed with a saturated aqueous solution of sodium bicarbonate and withbrine, dried (MgSO₄) and evaporated. There was thus obtained the titlecompound as a solid (0.086 g);

[0453] NMR Spectrum: (CDCl₃) 2.26 (s, 3H), 3.94 (s, 6H), 6.91 (d, 1H),7.18 (d, 1H), 7.29-7.81 (m, 8H), 8.09 (m, 2H); Mass Spectrum: M+H⁺ 425.

[0454] The N-[5-amino-2-methylphenyl]-3,4-dimethoxybenzamide used asstarting material was prepared as follows:—

[0455] A solution of 3,4-dimethoxybenzoyl chloride (11.5 g) in methylenechloride (100 ml) was added dropwise to a stirred mixture of2-methyl-5-nitroaniline (8.74 g), pyridine (18.6 ml) and methylenechloride (200 ml) and the mixture was stirred at ambient temperature for18 hours. The mixture was washed with 2N hydrochloric acid and withwater, dried (MgSO₄) and evaporated. The resultant solid was dried undervacuum at 60° C. There was thus obtainedN-(2-methyl-5-nitrophenyl)-3,4-dimethoxybenzamide (15.9 g), m.p.>300°C.;

[0456] NMR Spectrum: (CDCl₃) 2.43 (s, 3H), 3.94 (in, 6H), 6.93 (m, 1H),7.38 (m, 2H), 7.51 (m, 1H), 7.75 (br s, 1H), 7.94 (d, 1H), 8.89 (br m,1H).

[0457] 10% Palladium-on-carbon (4 g) was added to a stirred suspensionof the material so obtained in methanol (1500 ml) and the mixture wasstirred under an atmosphere of hydrogen gas. After cessation of hydrogenuptake, the catalyst was removed by filtration and the filtrate wasevaporated. The residue was washed with diethyl ether and dried undervacuum at 60° C. There was thus obtained the required starting material(11.3 g), m.p. 157-158° C.;

[0458] NMR Spectrum: (CDCl₃) 2.24 (s, 3H), 3.64 (br s, 2H), 3.95 (m,6H), 6.44 (m, 1H), 6.93 (d, 1H), 6.98 (d, 1H), 7.38 (m, 1H), 7.54 (m,2H), 7.6 (br s, 1H).

EXAMPLE 6

[0459] N-[5-(3-bromobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0460] 3-Bromobenzoyl chloride (1.53 g) was added to a stirred mixtureof N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (2 g), pyridine(1.7 ml) and methylene chloride (40 ml) and the mixture was stirred atambient temperature for 18 hours. The precipitated solid was isolated,washed with diethyl ether and dried under vacuum at 60° C. There wasthus obtained the title compound (1.89 g);m.p. 136-138° C.;

[0461] NMR Spectrum: (DMSOd₆) 2.18 (s, 3H), 3.81 (s, 6H), 7.05 (d, 1H),7.23 (d, 1H), 7.45 (t, 1H), 7.56 (m, 2H), 7.63 (m, 1H), 7.78 (m, 2H),7.95 (d, 1H), 8.13 (d, 1H) 9.75 (br s, 1H), 10.31 (br s, 1H); MassSpectrum: M+H⁺ 469;

[0462] Elemental Analysis: Found: C, 59.1; H, 4.4; N, 5.9;

[0463] C₂₃H₂₁N₂O₄Br requires C, 58.9; H, 4.5; N, 6.0%.

EXAMPLE 7

[0464] N-[5-benzamido-2-methylphenyl]-3,4-dimethoxybenzamide

[0465] 3,4-Dimethoxybenzoyl chloride (0.3 g) was added to a stirredmixture of N-(3-amino-4-methylphenyl)benzamide (0.23 g), triethylamine(0.4 ml) and methylene chloride (10 ml) and the mixture was stirred atambient temperature for 16 hours. The precipitate was isolated, washedwith water and with diethyl ether, dried under vacuum at 40° C. Therewas thus obtained the title compound (0.319 g);

[0466] NMR Spectrum: (DMSOd₆) 2.18 (s, 3H), 3.82 (s, 6H), 7.06 (d, 1H),7.25 (d, 1H), 7.55 (m, 6H), 7.82 (s, 1H), 7.94 (d, 2H), 9.76(s, 1H),10.20 (s, 1H); Mass Spectrum: M+H⁺ 391.

[0467] The N-(3-amino-4-methylphenyl)benzamide used as a startingmaterial was prepared as follows:—

[0468] Benzoyl chloride (1.9 ml) was added to a stirred mixture of2,4-diaminotoluene (2 g), triethylamine (5.57 ml) and methylene chloride(80 ml) and the mixture was stirred at ambient temperature for 16 hours.The mixture was washed with a saturated aqueous solution of sodiumbicarbonate. The organic phase was dried (MgSO₄) and evaporated. Theresidue was triturated with a mixture of ethyl acetate and diethylether. There was thus obtained the required starting material (1.32 g);NMR Spectrum: (DMSOd₆) 2.01 (s, 3H), 4.8 (s, 2H), 6.82 (m 2H), 7.11 (s,1H), 7.5 (m, 3H), 7.91 (m, 2H), 9.86 (s, 1H), Mass Spectrum: M+H⁺ 227.

EXAMPLE 8

[0469]N-(5-(3,4-dimethoxybenzamido)-2-methylphenyl]-3-dimethylaminobenzamide

[0470] Oxalyl chloride (1.14 g) was added to a stirred mixture of3-dimethylaminobenzoic acid (1.23 g), DMF (1 drop) and methylenechloride (40 ml) and the mixture was stirred at ambient temperature for3 hours. The solvent was evaporated and the residue was dissolved inmethylene chloride (40 ml). The resultant solution was added dropwise toa stirred mixture of N-(3-amino-4-methylphenyl)-3,4-dimethoxybenzamide(1.78 g), pyridine (3.77 ml) and methylene chloride (20 ml) and themixture was stirred at ambient temperature for 48 hours. The reactionmixture was washed in turn with water, a saturated aqueous sodiumbicarbonate solution, brine and water. The organic solution was dried(MgSO₄) and evaporated. The solid so obtained was recrystallised fromethyl acetate and dried under vacuum at 60° C. There was thus obtainedthe title compound (0.359 g), m.p. 204-205° C.;

[0471] NMR Spectrum: (DMSOd₆) 2.28 (s, 3H), 3.01 (s, 6H), 3.93 (d, 6H),6.88 (m, 2H), 7.09 (d, 1H), 7.18 (d, 1H), 7.26 (s, 1H), 7.33 (t, 1H),7.41 (m, 1H); 7.5 (d, H), 7.76 (m, 2H), 8.05 (br s, 1H), 8.13 (d, 1H);Mass Spectrum: M+H⁺ 434.

[0472] The N-(3-amino-4-methylphenyl)-3,4-dimethoxybenzamide used asstarting material was prepared as follows:—

[0473] A solution of 3,4-dimethoxybenzoyl chloride (13.2 g) in methylenechloride (200 ml) was added dropwise to a stirred mixture of4-methyl-3-nitroaniline (10 g), pyridine (21.3 ml),4-dimethylaminopyridine (0.4 g) and methylene chloride (100 ml) and theresultant solution was stirred at ambient temperature for 18 hours. Thereaction mixture was washed with 2N hydrochloric acid and water dried(MgSO₄) and evaporated. The residue was triturated under diethyl etherand the resultant solid was dried under vacuum at 60° C. There was thusobtained N-(4-methyl-3-nitrophenyl)-3.4-dimethoxybenzamide (18.1 g),m.p. 148-149° C.;

[0474] NMR Spectrum: (CDCl₃) 2.58 (s, 3H), 3.96 (s, 6H), 6.92 (d, 1H),7.33 (d, 1H), 7.43 (m, 1H), 7.51 (d, 1H), 7.9 (m, 1H), 7.97 (br s, 1H),8.24 (d, 1H).

[0475] Ammonium formate (33.9 g) was added to a stirred suspension ofN-(4-methyl-3-nitrophenyl)-3,4-dimethoxybenzamide (17 g) and 10%palladium-on-carbon (4 g) in ethanol (650 ml) and the mixture wasstirred and heated to reflux for 1.5 hours. The reaction mixture wasallowed to cool to ambient temperature and filtered. The filtrate wasevaporated and the residue was partitioned between methylene chlorideand a saturated aqueous sodium bicarbonate solution. The organic phasewas washed with water, dried (MgSO₄) and evaporated. The residue wastriturated under diethyl ether and the resultant solid was dried undervacuum at 60° C. There was thus obtained the required starting material(12.6 g), m.p. 143-144° C., NMR Spectrum: (CDCl₃) 2.13 (s, 3H), 3.65 (brs, 2H), 3.93 (s, 6H), 6.73 (m, 1H), 6.93 (d, 1H), 6.87 (m, 1H), 7.0 (m,1H), 7.28 (d, 1H), 7.36 (m, 1H), 7.48 (d, 1H), 7.7 (br s, 1H).

EXAMPLE 9

[0476] Using an analogous procedure to that described in Example 3, 5, 6or 7, the appropriate benzoyl chloride was reacted with the appropriateaniline to give the compounds described in Table I. With reference tothe chemical formula immediately hereinafter in Table I and when ananalogous procedure to that described in Example 3, 5 or 6 is employed,the appropriate benzoyl chloride is of the formula R—C₆H₄—COCl and whenan analogous procedure to that described in Example 7 is employed, theappropriate benzoyl chloride is of the formula (R¹)_(m)—C₆H_((5-m))—COClTABLE I

No. (R¹)_(m) R Method Note 1 3,4-dimethoxy 4-bromo Ex. 6 a 23,4-dimethoxy 4-fluoro Ex. 6 b 3 3,4-dimethoxy 3-benzyloxy Ex. 6 c 43,4-dimethoxy 4-benzvloxy Ex. 6 d 5 3,4-dimethoxy 3-nitro Ex. 6 e 63,4-dimethoxy 4-cyano Ex. 5 f 7 3,4-dimethoxy 3-dimethylamino Ex. 7 g 83,4-dimethoxy 4-morpholino Ex. 6 h 9 3,4-dimethoxy 4-(4-thiamorpholino)Ex. 6 i 10 3,4-dimethoxy 3,4-dimethoxy Ex. 5 j 11 4-hydroxy hydrogen Ex.3 k 12 4-hydroxy 2-fluoro-6-chloro Ex. 3 1 13 4-hydroxy 4-benzyloxy Ex.3 m 14 4-hydroxy 3,5-dimethoxy Ex. 3 n 15 4-hydroxy 4-phenyl Ex. 3 o 164-hydroxy 4-nitro Ex. 3 p 17 4-acetoxy 4-cyano Ex. 7 q 18 4-propyl3-dimethylamino Ex. 7 r 19 4-ethyl 3-dimethylamino Ex. 7 S 204-tert-butyl 3-dimethylamino Ex. 7 t 21 4-butyl 3-dimethylamino Ex. 7 u22 3,4-dimethyl 3-dimethylamino Ex. 7 v 23 2-methoxy 3-dimethylamino Ex.7 w 24 3-methoxy 3-dimethylamino Ex. 7 x 25 4-methoxy 3-dimethylaminoEx. 7 y 26 3-ethoxy 3-dimethylamino Ex. 7 z 27 4-ethoxy 3-dimethylaminoEx. 7 aa 28 4-isopropoxy 3-dimethylamino Ex. 7 bb 29 3-butoxy3-dimethylamino Ex. 7 cc 30 2.4-dimethoxy 3-dimethylamino Ex. 7 dd 313,4-diethoxy 3-dimethylamino Ex. 7 ee 32 3,4,5-trimethoxy3-dimethylamino Ex. 7 ff 33 3-chloro 3-dimethylamino Ex. 7 gg 344-chloro 3-dimethylamino Ex. 7 hh 35 2-fluoro 3-dimethylamino Ex. 7 ii36 3,5-difluoro 3-dimethylamino Ex. 7 jj 37 3-trifluoromethyl3-dimethylamino Ex. 7 kk 38 4-trifluoromethyl 3-dimethylamino Ex. 7 ll39 3-cyano 3-dimethylamino Ex. 7 mm 40 4-cyano 3-dimethylamino Ex. 7 nn41 4-methoxycarbonyl 3-dimethylamino Ex. 7 oo 42 4-cyano 4-cyano Ex. 5pp 43 hydrogen hydrogen Ex. 7 qq 44 3,4,5-trimethoxy 4-cyano Ex. 7 rr 453,4,5-trimethoxy hydrogen Ex. 7 ss 46 3,4,5-trimethoxy 3-trifluoromethylEx. 7 tt 47 3,4,5-trimethoxy 3-morpholino Ex. 6 uu 48 3-bromo3-dimethylamino Ex. 6 vv 49 3-nitro 3-dimethylamino Ex. 6 ww 503-morpholino 3-morpholino Ex. 6 xx 51 3-(4-methylpiperazin-1-yl)methylhydrogen Ex. 5 yy 52 3-(4-methylpiperazin-1-yl)methyl 3-trifluoromethylEx. 5 zz 53 3-(4-methylpiperazin-1-yl)methyl 2-fluoro Ex. 5 aaa 543-(4-methylpiperazin-1-yl)methyl 4-fluoro Ex. 5 bbb 553-(4-methylpiperazin-1-yl)methyl 2-chloro Ex. 5 ccc 563-(4-methylpiperazin-1-yl)methyl 3-chloro Ex. 5 ddd 573-(4-methylpiperazin-1-yl)methyl 4-chloro Ex. 6 eee 583-(4-methylpiperazin-1-yl)methyl 2,5-difluoro Ex. 6 fif 593-(4-methylpiperazin-1-yl)methyl 3,5-difluoro Ex. 5 ggg 603-(4-methylpiperazin-1-yl)methyl 2,4-dichloro Ex. 5 hhh 613-(4-methylpiperazin-1-yl)methyl 3,4-dichloro Ex. 5 iii 623-(4-methylpiperazin-1-yl)methyl 2-methoxy Ex. 6 jjj 633-(4-methylpiperazin-1-yl)methyl 4-methoxy Ex. 5 kkk 643-(4-methylpiperazin-1-yl)methyl 3-ethoxy Ex. 5 111 653-(4-methylpiperazin-1-yl)methyl 3,4-dimethoxy Ex. 5 mmm 663-(4-methylpiperazin-1-yl)methyl 3-cyano Ex. 5 nnn 673-(4-methylpiperazin-1-yl)methyl 4-methoxycarbonyl Ex. 5 000 683-(4-methylpiperazin-1-yl)methyl 3-morpholino Ex. 5 ppp

[0477] The N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide used asstarting material was prepared as follows:

[0478] Oxalyl chloride (13.0 ml) was added dropwise to a stirred mixtureof 3-dimethylaminobenzoic acid (20.3 g) and DMF (a few drops) which hadbeen cooled to 0° C. The mixture was allowed to warm to ambienttemperature and was stirred for 4 hours. The resultant mixture wasevaporated and the residue was dissolved in methylene chloride (150 ml).4-Methyl-3-nitroaniline (15.2 g) and triethylamine (27.9 ml) were addedin turn and the resultant mixture was stirred at ambient temperature for16 hours. The reaction mixture was washed in turn with water, with asaturated solution of sodium bicarbonate and with brine, dried (MgSO₄)and evaporated. The residue was triturated under a mixture of ethylacetate and isohexane. The solid so obtained was filtered off andrecrystallised from ethanol to giveN-(3-nitro-4-methylphenyl)-3-dimethylaminobenzamide (6.1 g); NMR(DMSOd₆) 2.46 (s, 3H), 2.95 (s, 6H), 6.92 (d, 1H), 7.22 (m, 2H), 7.32(t, 1H), 7.45 (d, 1H), 7-97 (d, 1H), 8.53 (s, 1H), 10.43 (s, 1H); MassM+H⁺ 300;

[0479] After repetition of the previous reactions, a sample (8.25 g) wasadded to a stirred suspension of ammonium formate (17.4 g), and 10%palladium-on-carbon (1 g) in methanol (250 ml). The mixture was stirredand heated to reflux for 4 hours. The mixture was allowed to cool andthen filtered. The filtrate was evaporated and water was added to theresidue. The resultant solid was isolated and washed in turn with water,with ethyl acetate and with diethyl ether. The solid was dried in avacuum oven at 40° C. to giveN-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (6.89 g);

[0480] NMR (DMSOd₆) 2.0 (s, 3H), 2.94 (s, 6H), 4.78 (s, 2H), 6.82 (m,3H), 7.07 (s, 1H), 7.17 (m, 2H), 7.25 (m, 1H), 9.74 (s, 1H); Mass M+H⁺270.

[0481] h) The reactants were 4-morpholinobenzoyl chloride andN-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide. The product gave thefollowing data: m.p. 226-228° C.;

[0482] NMR (DMSOd₆) 2.18 (s, 3H), 3.23 (t, 4H), 3.76 (t, 4H), 3.82 (s,6H), 7.01 (d, 2H), 7.08 (d, 1H), 7.19 (d, 1H), 7.56 (m, 2H), 7.62 (d,1H), 7.79 (s, 1H), 7.88 (d, 2H), 9.75 (s, 1H), 9.95 (s, 1H); Mass M+H⁺476.

[0483] The 4-morpholinobenzoyl chloride used as a starting material wasprepared as follows:—

[0484] Morpholine (2.16 g) was added to a stirred mixture of benzyl4-fluorobenzoate (3.1 g), potassium carbonate (4.48 g) and DMSO (45 ml)and the reaction mixture was heated to 100° C. for 36 hours. The mixturewas cooled to ambient temperature and partitioned between diethyl etherand water. The organic phase was washed with brine dried (MgSO₄) andevaporated. The residue was recrystallised from a 3:1 mixture of hexaneand ethyl acetate to give benzyl 4-morpholinobenzoate (2.24 g) as acolourless solid, m.p. 85-86° C.; NMR Spectrum: (CDCl₃) 3.19 (t, 4H),3.77 (t, 4H), 5.23 (s, 2H), 6.78 (d, 2H), 7.30 (m, 5H), 7.9 (d, 2H).

[0485] Palladium-on-carbon catalyst (0.12 g) was added to a stirredsolution of the above benzyl ester (1.50 g) in a mixture of ethanol (100ml) and ethyl acetate (15 ml). The mixture was stirred under anatmosphere of hydrogen. After cessation of hydrogen uptake, the catalystwas removed by filtration and the filter cake was washed with ethanol.The combined filtrates were evaporated to give 4-morpholinobenzoic acid(0.69 g); NMR Spectrum: (DMSOd₆) 3.22 (t, 4H), 3.72 (t, 4H), 6.96 (d,2H), 7.78 (d, 2H).

[0486] Oxalyl chloride (0.062 ml) was added dropwise to a stirredsuspension of 4-morpholinobenzoic acid (0.113 g) in methylene chloride(5 ml) which had been cooled to 0° C. DMF (1 drop) was added and themixture was stirred at ambient temperature for 4 hours. The solvent wasevaporated to give 4-morpholinobenzoyl chloride which was used withoutfurther purification.

[0487] i) The product gave the following data: m.p. 236-238° C.; NMR(DMSOd₆) 2.18 (s, 3H), 2.61 (t, 4H), 3.72 (t, 4H), 3.82 (s, 6H), 6.95(d, 2H), 7.06 (d, 1H), 7.18 (d, 1H), 7.56 (m, 2H), 7.62 (d, 1H), 7.8 (s,1H) 7.82 (d, 2H), 9.75 (s 1H), 9.9 (s, 1H); Mass M+H 492.

[0488] The 4-(4-thiamorpholino)benzoyl chloride used as a startingmaterial was prepared as follows:—

[0489] Ethyl 4-(4-thiamorpholino)benzoate was prepared from ethyl4-fluorobenzoate and thiamorpholine using an analogous procedure to thatdescribed in Note h) for the preparation of benzyl 4-morpholinobenzoate.The material so obtained had m.p. 46.5-47.5° C. and NMR (CDCl₃) 1.3 (t,3H), 2.62 (t: 4H), 3.63 (t, 4H), 4.23 (m, 2H), 6.78 (d, 2H), 7.82 (d,2H).

[0490] Ethyl 4-(4-thiamorpholino)benzoate (1.02 g) was added to asolution of sodium hydroxide (0.32 g) in 90% ethanol (10 ml) and thesolution was stirred at ambient temperature for 18 hours. The ethanolwas evaporated and 1N hydrochloric acid (8 ml) was added to the residue.The mixture was stirred for 1 hour. The precipitate was isolated andwashed with water. The material was triturated under ethyl acetate togive 4-(4-thiamorpholino)benzoic acid (0.66 g) as a colourless solid,m.p. 238-240° C.;

[0491] NMR (DMSOd₆) 2.6 (t, 4H), 3.73 (t, 4H), 6.91 (d, 2H), 7.75 (d,2H), 12.2 (s, 1H).

[0492] The acid so obtained was converted into the required benzoylchloride using an analogous procedure to that described in Note h).

[0493] j) The reactants were 3,4-dimethoxybenzoyl chloride and2,4-diaminotoluene. The product gave the following data: NMR (DMSOd₆)2.18 (s, 3H), 3.82 (s, 12H), 7.06 (d, 2H), 7.21 (d, 1H), 7.57 (m, 5H),7.76 (s, 1H), 9.74 (s, 1H), 10.01 (s, 1H); Mass M+H⁺ 451.

[0494] k) The reactants were benzoyl chloride andN-(5-amino-2-methylphenyl)-4-hydroxybenzamide. The product gave thefollowing data: NMR (DMSOd₆) 2.2 (s, 3H), 6.87 (d, 2H), 7.21 (d, 1H),7.56 (m, 4H), 7.9 (m, 5H), 9.6 (s, 1H), 10.0 (s, 1H), 10.2 (s, 1H); MassM+H 347.

[0495] l) The product gave the following data: Mass M+H 399.

[0496] m) The product gave the following data: NMR (DMSOd₆) 2.19 (s,3H), 5.2 (s, 2H)) 6.68 (d, 2H), 7.15 (m, 3H), 7.4 (m, 5H), 7.58 (m, 1H),7.8 (d, 1H), 7.88 (d, 2H), 7.95 (d, 2H), 9.6 (s, 1H), 10.02 (s, 1H),10.05 (s, 1H); Mass M+H⁺ 453.

[0497] n) The product gave the following data: Mass M+H⁺ 407.

[0498] o) The product gave the following data: NMR (DMSOd₆) 2.21 (s,3H), 6.87 (d, 2H), 7.22 (d, 1H), 7.48 (m, 4H), 7.61 (m, 1H), 7.8 (m,6H), 8.08 (d, 2H), 9.63 (s, 1H), 10.05 (s, 1H) 10.25 (s, 1H); Mass M+H⁺423.

[0499] p) The product gave the following data: NMR (DMSOd₆) 2.18 (s,3H), 3.68 (s, 2H), 6.86 (d, 2H), 7.17 (d, 1H), 7.35 (m, 2H), 7.6 (m,3H), 7.86 (d, 2H), 9.54 (s, 1H), 9.99 (s, 1H), 10.12 (s, 1H); Mass M+H⁺406.

[0500] q) The reactants were 4-acetoxybenzoyl chloride andN-(3-amino-4-methylphenyl)-4-cyanobenzamide. 4-Dimethylaminopyridine(0.15 equivalents) was added to catalyse the reaction. The product gavethe following data: NMR (DMSOd₆) 2.18 (s, 3H), 2.26 (s, 3H), 7.25 (m,3H), 7.57 (d, 1H), 7.84 (s, 1H), 8.0 (m, 4H), 8.11 (d, 2H), 9.91 (s,1H), 10.46 (s, 1H); Mass: (M−H) 412.

[0501] The N-(3-amino-4-methylphenyl)-4-cyanobenzamide used as startingmaterial was prepared as follows:

[0502] Triethylamine (23 ml) was added to a suspension of3-nitro-4-methylaniline (0.8 g), 4-cyanobenzoyl chloride (13.1 g),4-dimethylaminopyridine (0.8 g) in methylene chloride (200 ml) which hadbeen cooled to 0° C. The reaction mixture was allowed to warm to ambienttemperature and was stirred for 5 hours. The mixture was partitionedbetween methylene chloride 0.5N hydrochloric acid solution. The organicphase was dried (MgSO₄) and evaporated and the residue was trituratedunder isohexane. The solid was isolated and dried under vacuum at 55° C.There was thus obtained (3-nitro-4-methylphenyl)-4-cyanobenzamide (18.3g); NMR (DMSOd₆) 2.5 (s, 3H), 7.49 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H),8.12 (d, 2H), 8.51 (d, 1H), 10.77 (s, 1H).

[0503] A solution of tin(II) chloride dihydrate (15.4 g) in concentratedhydrochloric acid (80 ml) was added to a suspension ofN-(3-nitro-4-methylphenyl) -4-cyanobenzamide (6.39 g) in acetic acid(120 ml). The mixture was stirred and heated to reflux for 2 hours. Themixture was allowed to cool to ambient temperature and was basified bythe addition of 2N sodium hydroxide solution. The precipitated solid wasisolated and dried under vacuum at 55° C. to giveN-(3-amino-4-methylphenyl)-4-cyanobenzamide (5.62 g); NMR (DMSOd₆) 2.01(s, 3H), 4.85 (s, 2H), 6.80 (d, 1H), 6.86 (d, 1H), 7.11 (s, 1H), 7.96(d, 2H), 8.06 (d, 2H), 10.11 (s, 1H).

[0504] r) The reactants were 4-propylbenzoyl chloride andN-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide. The product gavethe following data: NMR (DMSOd₆) 0.89 (m, 3H), 1.61 (m, 2H), 2.19 (s,3H), 2.62 (m, 2H), 2.95 (s, 6H), 6.89 (d, 1H), 7.22 (m, 3H), 7.30 (m,3H), 7.57 (m, 1H), 7.78 (m, 1H), 7.9 (m, 2H), 9.8 (s, 1H), 10.08 (s,1H); Mass M+H 416.

[0505] s) The product gave the following data: Mass M+H 402.

[0506] t) The product gave the following data: NMR (DMSOd₆) 2.18 (s,31H), 2.94 (s, 6H), 6.9 (d, 1H), 7.20 (m, 3H), 7.28 (t, 1H), 7.55 (m,3H), 7.8 (s, 1H), 7.91 (d, 2H), 9.79 (s, 1H), 10.08 (s, 1H); Mass M+H430.

[0507] u) The product gave the following data: Mass M+H 430.

[0508] v) The product gave the following data: Mass M+H 402.

[0509] w) The product gave the following data: NMR (DMSOd₆) 2.28 (s,3H), 2.95 (s, 6H), 3.99 (s, 31H), 6.9 (m, 1H), 7.11 (m, 1H), 7.25 (m,5H), 7.55 (m, 2H), 7.9 (d, 1H), 8.33 (s, 1H), 9.81 (s, 1H), 10.09 (s,1H); Mass M+H 404.

[0510] x) The product gave the following data: NMR (DMSOd₆) 2.29 (s,31H), 3.0 (s, 6H), 3.87 (s, 3H), 6.86 (m, 1H), 7.1 (m, 2H), 7.2 (d, 1H),7.28 (m, 2H), 7.4 (m, 2H), 7.45 (br s, 1H), 7.72 (m, 1H), 7.77 (br s,1H), 7.98 (br s, 1H), 8.08 (d, 1H); Mass M+H 404.

[0511] y) The product gave the following data: NMR (DMSOd₆) 2.18 (s,3H), 2.94 (s, 6H), 3.82 (s, 31H), 6.89 (d, 1H), 7.04 (d, 2H), 7.2 (m,3H), 7.29 (td, 1H), 7-56 (d, 1H), 7.78 (s, 1H), 7.95 (d, 2H), 9.72 (s,1H), 10.07 (s, 1H); Mass M+H 404.

[0512] z) The product gave the following data: Mass M+H 418.

[0513] aa) The product gave the following data: Mass M+H 418.

[0514] bb) The product gave the following data: NMR (DMSOd₆) 1.28 (d,6H), 2.18 (s, 3H), 2.95 (s, 6H), 4.72 (m, 1H), 6.89 (d, 1H), 7.01 (d,2H), 7.19 (m, 31H), 7.27 (m, 1H), 7.56 (d, 1H), 7.78 (s, 1H), 7.93 (d,2H), 9.7 (s, 1H), 10.08 (s, 1H); Mass M+H 432.

[0515] cc) The product gave the following data: NMR (DMSOd₆) 0.93 (t,3H), 1.44 (m 2H), 2.71 (m, 2H), 2.18 (s, 3H), 2.94 (s, 6H), 4.04 (t, 2H)6.9 (d, 1H), 7.03 (d, 2H), 7.26 (m, 4H), 7.56 (d, 1H), 7.8 (s, 1H), 7.94(d, 2H), 9.71 (s, 1H), 10.08 (s, 1H); Mass M+H 446.

[0516] dd) The product gave the following data: NMR (DMSOd₆) 2.27 (s,3H), 2.95 (s, 6H), 3.85 (s, 3H), 4.05 (s, 3H), 6.72 (m, 2H), 6.89 (d1H), 7.22 (m, 4H), 7.51 (d, 1H), 7.95 (d, 1H), 8.42 (d, 1H), 9.72 (s,1H), 10.01 (s, 1H); Mass M+H 434.

[0517] ee) The product gave the following data: Mass M+H 462. The3.4-diethoxybenzoyl chloride used as a starting material was prepared bythe reaction of 3,4-diethoxybenzoic acid and oxalyl chloride.

[0518] ff) The product gave the following data: NMR (DMSOd₆) 2.18 (s,3H), 2.94 (s, 6H), 3.72 (s, 3H), 3.84 (s, 6H), 6.89 (d, 1H), 7.25 (m,6H), 7.56 (d, 1H), 7.77 (s, 1H), 9.86 (s, 1H), 10.09 (s, 1H); Mass M+H464.

[0519] gg) The product gave the following data: Mass M+H 408.

[0520] hh) The product gave the following data: Mass M+H 408.

[0521] ii) The product gave the following data: NMR (DMSOd₆) 2.22 (s,3H), 2.95 (s, 6H), 6.9 (d, 1H), 7.26 (m, 6H), 7.56 (m, 2H), 7.71 (t,1H), 7.92 (s, 1H), 9.82 (s, 1H), 10.I (s, 1H); Mass M+H 392.

[0522] jj) The product gave the following data: NMR (DMSOd₆) 2.18 (s,3H), 2.95 (s, 6H), 6.89 (d,1H), 7.25 (m, 4H), 7.55 (m, 2H), 7.63 (m,2H), 7.79 (s, 1H), 10.06 (s, 1H), 10.1 (s, 1H); Mass M+H 410.

[0523] kk) The product gave the following data: NMR (DMSOd₆) 2.19 (s,3H) 2.95 (s, 6H) 6.9 (d, 1H), 7.24 (m, 4H), 7.58 (d, 1H) 7.78 (m, 2H),7.96 (d, 1H), 8.28 (d, 2H) 10.11 (s, 1H), 10.19 (s, 1H); Mass M+H 442.

[0524] ll) The product gave the following data: Mass M+H 442.

[0525] mm) The product gave the following data: NMR (DMSOd₆) 2.19 (s,3H), 2.95 (s, 6H), 6.89 (d, 1H), 7.24 (m, 4H), 7.58 (d, 1H), 7.75 (t,1H), 7.81 (s, 1H), 8.06 (d, 1H), 8.23 (d, 1H), 8.4 (s, 1H), 10.11 (s,2H); Mass M+H 399.

[0526] nn) The product gave the following data: Mass M+H 399.

[0527] oo) The product gave the following data: NMR (DMSOd₆) 2.19 (s,3H), 2.95 (s, 6H), 3.89 (s, 3H), 6.89 (d, 1H), 7.25 (m, 4H), 7.57 (d,1H), 7.8 (s, 1H), 8.08 (s, 4H), 9.8 (s, 1H), 10.1 (s, 1H); Mass M+H 432.

[0528] pp) The reactants were 4-cyanobenzoyl chloride and2,4-diaminotoluene. The product gave the following data: NMR (DMSOd₆)2.02 (s, 3H), 7.44 (d, 1H), 7.59 (d, 1H), 7.84 (d, 1H), 8.0 (m, 4H), 8.1(m, 4H), 10.16 (s, 1H), 10.48 (s, 1H); Mass M+H 381.

[0529] qq) The reactants were benzoyl chloride and 2.4-diaminotoluene.The minor product was N-(5-benzamido-2-methylphenyl)benzamide which gavethe following data: NMR (DMSOd₆) 2.2 (s, 3H), 7.21 (d, 1H), 7.5 (m, 7H),7.84 (s, 1H), 7.98 (m, 4H), 9.81 (s, 1H), 10.23 (s, 1H); Mass M+H 331.The major product was N-(3-amino-4-methylphenyl)benzamide which gave thefollowing data: NMR (DMSOd₆) 2.01 (s, 3H), 4.80 (s, 2H), 6.82 (m 2H),7.11 (s, 1H), 7.5 (m, 3H), 7.91 (m, 2H), 9.86 (s, 1H); Mass M+H 227.

[0530] rr) The reactants were 3,4.5-trimethoxybenzoyl chloride andN-(3-amino-4-methylphenyl)-4-cyanobenzamide. 4-Dimethylaminopyridine(0.1 equivalents) was added to catalyse the reaction. On completion ofthe reaction, the reaction mixture was evaporated and the residue wastriturated under 2N aqueous hydrochloric acid. The resultant solid wasisolated, washed with a saturated aqueous sodium bicarbonate solutionand with water and dried under vacuum at 55° C. The product gave thefollowing data: NMR (DMSOd₆) 2.2 (s, 3H), 3.72 (s, 3H), 3.85 (s, 6H),7.25 (d 1H), 7.33 (s, 2H), 7.56 (d, 1H), 7.81 (s, 1H), 8.0 (d, 2H), 8.1(d, 2H), 9.87 (s, 1H), 10.46 (s, 1H); Mass M−H 444.

[0531] ss) 4-Dimethylaminopyridine (0.1 equivalents) was added tocatalyse the reaction and the work-up described in Note rr) was used.The product gave the following data: NMR (DMSOd₆) 2.19 (s, 3H), 3.73 (s,3H), 3.85 (s, 6H), 7.24 (d, 1H), 7.32 (s, 2H), 7.55 (m, 4H), 7.82 (s,1H), 7.94 (d, 2H), 9.86 (br s, 1H), 10.22 (br s, 1H); Mass M−H 419.

[0532] tt) 4-Dimethylaminopyridine (0.1 equivalents) was added tocatalyse the reaction and the work-up described in Note rr) was used.The product gave the following data: NMR (DMSOd₆) 2.2 (s, 3H), 3.73 (s,3H), 3.84 (s, 6H), 7.25 (d, 1H), 7.32 (s, 2H), 7.58 (d, 1H), 7.78 (m,2H), 7.95 (d, 1H), 8.25 (m, 2H), 9.86 (s, 1H), 10.44 (s, 1H); Mass M−H487.

[0533] uu) The reactants were 3-morpholinobenzoyl chloride andN-(5-amino-2-methylphenyl) -3.4,5-trimethoxybenzamide. On completion ofthe reaction, the reaction mixture was evaporated and the residue wasazeotroped with toluene. The resultant residue was stirred undermethanol for 30 minutes. The solid so obtained was isolated and dried.

[0534] The product gave the following data: NMR (DMSOd₆) 2.2 (s, 3H),3.2 (t, 4H), 3.74 (m, 7H), 3.84 (s, 6H), 7.13 (m, 1H), 7.22 (d, 1H),7.32 (s, 2H), 7.36 (d, 1H), 7.43 (s, 1H), 7.58 (d, 1H), 7.79 (s, 1H),9.84 (s, 1H), 10.12 (s, 1H); Mass M+H 506.

[0535] The 3-morpholinobenzoyl chloride used as a starting material wasprepared as follows:—

[0536] A mixture of ethyl 3-bromobenzoate (1.92 ml), morpholine (1.25ml), 2,2′-bis(diphenylphosphino)-1, -binaphthyl (0.336 g), sodiumtert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0)(0.33 g) and toluene (25 ml) was stirred and heated to 90° C. for 18hours under argon. The reaction mixture was allowed to cool to ambienttemperature and extracted with 1N aqueous hydrochloric acid. The aqueousphase was basified with concentrated sodium hydroxide solution andextracted with ethyl acetate. The organic phase was dried (MgSO₄) andevaporated. The residual oil was purified by column chromatography onsilica gel using a 47:3 mixture of methylene chloride and methanol aseluent. There was thus obtained N-(3-morpholinobenzoyl)morpholine (0.45g).

[0537] A mixture of the material so obtained. 5M sodium hydroxidesolution (2.5 ml) and butanol (2 ml) was stirred and heated to 11 5° C.for 18 hours. The mixture was evaporated and the residue was acidifiedby the addition of 1N aqueous hydrochloric acid solution (12.5 ml). Theresultant precipitate was isolated, washed with water and dried to give3-morpholinobenzoic acid (0.15 g); NMR (DMSOd₆) 3.1 (t, 4H), 3.73 (t,4H), 7.19 (d, 1H), 7.32 (d, 1H), 7.38 (t, 1H), 7.42 (s, 1H).

[0538] Oxalyl chloride (0.14 ml) was added to a solution of3-morpholinobenzoic acid (0.28 g) in methylene chloride (10 ml) whichcontained DMF (2 drops). The reaction mixture was stirred for 18 hoursat ambient temperature. The mixture was evaporated and azeotroped withtoluene to give 3-morpholinobenzoyl chloride (0.3 g); Mass M+H 222.

[0539] vv) The product gave the following data: m.p. 235-236° C.: NMR(DMSOd₆) 2.19 (s, 3H), 2.95 (s, 6H), 6.9 (m, 1H), 7.2 (m, 3H), 7.3 (t,1H), 7.48 (t,1H), 7.56 (m, 1H), 7.78 (m, 2H), 7.97 (d, 1H), 8.14 (d,1H), 10.02 (br s, 1H), 10.09 (br s, 1H); Mass M+H 453.

[0540] ww) The product gave the following data: m.p. 219-220° C.: NMR(DMSOd₆) 2.2 (s, 3H), 2.95 (s, 6H), 6.92 (d, 1H), 7.23 (m, 3H), 7.28 (t,1H), 7.575 (m, 1H), 7.83 (m, 2H), 8.43 (m, 2H), 8.8 (d, 1H), 10.12 (brs, 1H), 10.33 (br s, 1H); Mass M−H 417.

[0541] xx) On completion of the reaction, the reaction mixture waswashed with water and with a saturated aqueous sodium bicarbonatesolution. The mixture was evaporated and the residue was azeotroped withtoluene. The resultant residue was purified by column chromatographyusing a 9:1 mixture of methylene chloride and methanol as eluent. Theproduct gave the following data: NMR (DMSOd₆) 2.2 (s 3H), 3.19 (s, 8H),3.78 (s, 8H), 7.18 (d, 2H), 7.21 (d, 1H), 7.39 (m, 4H), 7.43 (s, 1H)7.50 (s, 1H) 7.58 (m, 1H),7.8 (s, 1H), 9.82 (s, 1H), 10.12 (s, 1H) MassM+H 501.

[0542] yy) The reactants were benzoyl chloride andN-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide. Oncompletion of the reaction, the reaction mixture was washed with waterand with a saturated aqueous sodium bicarbonate solution. The mixturewas evaporated and the residue was triturated under a mixture of diethylether and ethyl acetate. The product so obtained gave the followingdata: Mass M+H 443.

[0543] TheN-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamideused as starting material was prepared as follows

[0544] 3-Chloromethylbenzoyl chloride (24.8 ml) was added to a stirredmixture of 2-methyl-5-nitroaniline (26.6 g), triethylamine (49 ml) andmethylene chloride (800 ml) and the mixture was stirred at ambienttemperature for 16 hours. The precipitate was isolated, washed with 1Naqueous hydrochloric acid solution and with diethyl ether and driedunder vacuum at 40° C. There was thus obtained3-chloromethyl-N-(2-methyl-5-nitrophenyl)benzamide (43.5 g); NMR(DMSOd₆) 2.38 (s 3H), 2.85 (s, 2H), 7.53-7.58 (m, 2H), 7.67 (d, 1H),7.95(d, 1H), 8.01-8.04 (m, 2H), 8.32 (s, 1H), 10.19 (s, 1H); Mass M+H⁺305.

[0545] 1-Methylpiperazine (8.03 ml) was added to a stirred mixture of aportion (20 g) of the material so obtained, potassium carbonate (18.2 g)and acetone (750 ml) and the mixture was heated to 54° C. and stirredfor 16 hours. The resultant solution was evaporated and the residue wasdissolved in methylene chloride. The organic solution was washed withwater and evaporated. There was thus obtainedN-(2-methyl-5-nitrophenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide(26.4 g); NMR (DMSOd₆) 2.06 (s, 3H), 2.12 (s, 3H), 2.31-2.37 (m, 8H),3.52 (s, 2H), 7.48-7.57 (m, 3H), 7.87 (d, 2H), 8.01 (m, 1H), 8.33 (s,1H); Mass M+H⁺ 369.

[0546] Iron powder was added to a stirred mixture of a portion (18.0 g)of the material so obtained, ethanol (500 ml), water (50 ml) and aceticacid (10 ml). The resultant mixture was stirred and heated to reflux for5 hours. Water (50 ml) was added and the mixture was basified by theaddition of sodium carbonate. The mixture was filtered and the filtratewas evaporated to dryness. The residue was triturated under water andthe resultant solid was isolated and dried under vacuum at 40° C. Therewas thus obtainedN-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide(11.1 g); NMR (DMSOd₆) 2.03 (s, 3H), 2.13 (s, 3H), 2.24-2.4 (m, 8H), 3.5(s, 2H), 4.86 (s, 2H) 6.35 (d, 1H), 6.57 (s, 1H), 6.86 (d, 1H),7.40-7.48 (m, 2H), 7.78-7.83 (m, 2H), 9.57 (s, 1H): Mass M+H⁺ 339.

[0547] zz) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 511.

[0548] aaa) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 461.

[0549] bbb) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 461.

[0550] ccc) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 477.

[0551] ddd) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 477.

[0552] eee) The following variation of the procedure of Example 6 wasused. A mixture of 4-chlorobenzoyl chloride (0.4 mmol),N-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide(0.44 mmol) and pyridine (5 ml) was stirred and heated to 70° C. for 16hours. The resultant mixture was evaporated and the residue waspartitioned between methylene chloride and a saturated aqueous sodiumbicarbonate solution. The organic phase was evaporated and the residuewas triturated under ethyl acetate. The product so obtained gave thefollowing data: NMR (DMSOd₆) 2.13 (s, 3H), 2.19 (s, 3H), 2.25-2.37 (m,8H), 3.51 (s, 2H), 7.22 (d, 1H), 7.45-7.51 (m, 2H), 7.54-7.59 (m, 3H),7.81-7.87 (m, 3H), 7.97 (d, 2H), 9.88 (s, 1H), 10.28 (s, 1H); Mass M+H477.

[0553] fff) An analogous procedure to that described in Note eee) wasused. The product so obtained gave the following data: NMR (DMSOd₆) 2.13(s, 3H), 2.19 (s, 3H), 2.25-2.37 (m, 8H), 3.51 (s, 2H), 7.22 (d, 1H),7.38-7.58 (m, 6H), 7.75 (s, 1H), 7.85 (d, 2H), 9.88 (s, 1H) 10.44 (s,1H): Mass M+H 479.

[0554] ggg) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 479.

[0555] hhh) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 511.

[0556] iii) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 511.

[0557] jjj) An analogous procedure to that described in Note eee) wasused. The product so obtained gave the following data: NMR (DMSOd₆) 2.14(s, 3H), 2.17 (s, 3H), 2.25-2.4 (m, 8H), 3.51 (s, 2H) 3.88 (s, 3H), 7.05(t, 1H), 7.14-7.22 (m, 2H), 7.45-7.5 (m, 4H), 7.62 (d, 1H), 7.78 (s,1H), 7.85 (d, 2H), 9.9 (s, 1H), 10.06 (s, 1H); Mass M+H 473.

[0558] kkk) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 473.

[0559] lll) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 487.

[0560] mmm) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 503.

[0561] nnn) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 468.

[0562] ooo) The variation of the work-up described in Note yy) was used.The product so obtained gave the following data: Mass M+H 501.

[0563] ppp) The reactants were 3-morpholinobenzoyl chloride andN-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide. Oncompletion of the reaction, the reaction mixture was washed with waterand with a saturated aqueous sodium bicarbonate solution. The mixturewas evaporated and the residue was purified by column chromatography onan ion exchange column (isolute SCX column from International SorbentTechnology Limited, Hengoed, Mid-Glamorgan, UK) using a 99:1 mixture ofmethanol and a saturated aqueous ammonium hydroxide solution as eluent.The product so obtained gave the following data: NMR (DMSOd₆) 2.13 (s,3H), 2.19 (s, 3H), 2.31-2.38 (m, 8H), 3.15-3.18 (m, 4H), 3.52 (s, 2H),3.73-3.76 (m, 4H), 7.1-7.14 (m, 1H), 7.2 (d, 1H), 7.22-7.38 (m, 2H),7.4-7.52 (m, 3H), 7.52-7.6 (m, 1H), 7.4-7.87 (m, 2H), 9.84 (s, 1H) 10.11(s, 1H): Mass M+H 528.

EXAMPLE 10

[0564] N-[5-(4-hydroxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0565] 10% Palladium-on-carbon (0.5 g) was added to a stirred suspensionof N-[5-(4-benzyloxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide(3.97 g) in methanol (500 ml) and the mixture was stirred under anatmosphere of hydrogen. After cessation of hydrogen uptake, the mixturewas filtered and the filtrate was evaporated. The solid so obtained waswashed with diethyl ether and dried under vacuum at 60° C. There wasthus obtained the title compound (2.93 g), m.p. 258-259° C.;

[0566] NMR Spectrum: (DMSOd₆) 2.17 (s, 3H), 3.83 (s, 6H), 6.84 (d, 2H),7.05 (d, 1H), 7.19 (d, 1H), 7.54 (m, 2H), 7.65 (d, 1H), 7.78 (d, 1H)7.84 (d, 2H), 9.74 (br s, 1H), 9.93 (br s, 1H);

[0567] Mass Spectrum: M−H⁻ 405.

[0568] Elemental Analysis: Found C, 66.9; H, 5.3; N, 6.7;

[0569] C₂₃H₂₂N₂O₅.0.2H₂O requires C, 67.4; H, 5.5; N, 6.8%.

EXAMPLE 11

[0570] N-[5-(3-hydroxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0571] Using an analogous procedure to that described in Example 10,N-[5-(3-benzyloxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide washydrogenolysed to give the title compound in 72% yield; m.p. 182-183°C.; NMR Spectrum: (DMSOd₆) 2.17 (s, 3H), 3.83 (s, 6H), 6.95 (m, 1H),7.06 (d, 1H), 7.22 (d, 1H), 7.32 (m, 2H), 7.36 (d, 1H), 7.55 (m, 2H),7.63 (m, 1H), 7.82 (d, 1H), 9.68 (br s, 2H), 9.75 (br s, 1H), 10. 13 (brs, 1H); Mass Spectrum: M−H⁻ 405.

EXAMPLE 12

[0572] N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-acetylbenzamide

[0573] 4-Acetylbenzoic acid (0.164 g) was added to a stirred mixture ofN-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.135 g),diisopropylethylamine (0.325 nil),2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (0.39 g) and DMF (10 ml) and the mixture wasstirred at ambient temperature for 16 hours. The resultant solution wasevaporated. The residue was dissolved in methylene chloride and thesolution was washed in turn with water, a saturated aqueous solution ofsodium bicarbonate and brine, dried (MgSO₄) and evaporated The residuewas triturated under a mixture of ethyl acetate and isohexane. Theresultant solid was isolated, washed with ethyl acetate and dried undervacuum at 40° C. There was thus obtained the title compound as a solid(0.091 g); NMR Spectrum: (DMSO₆) 2.19 (s, 3H), 2.63 (s, 3H), 2.95 (s,6H), 6.91 (d, 1H), 7.29 (m, 4H), 7.62 (d, 1H), 7.82 (s, 1H), 8.1 (m,4H), 10.12 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H⁺ 416.

EXAMPLE 13

[0574] N-[5-(3-aminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0575] 10% Palladium-on-carbon (0.13 g) was added to a stirred solutionof N-[5-(3-nitrobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (1.27g) in methanol (150 ml) and the mixture was stirred under an atmospherepressure of hydrogen. After cessation of hydrogen uptake, the catalystwas removed by filtration and the filtrate was evaporated. The residuewas washed with diethyl ether and dried under vacuum at 60° C. There wasthus obtained the title compound (1.02 g), m.p. 179-180° C.;

[0576] NMR Spectrum: (DMSOd₆) 2.15 (s, 3H), 3.82 (s, 6H), 5.25 (s, 2H),6.72 (d, 1H), 7.05 (br m, 3H), 7.1 (t, 1H), 7.19 (d, 1H), 7.52 (m, 1H),7.55 (d, 1H), 7.63 (m, 1H), 7.79 (d, 1H), 9.76 (br s, 1H), 10.02 (br s,1H); Mass spectrum: M+H⁺ 406;

[0577] Elemental Analysis: Found C, 66.3; H, 5.3; N, 9.9;

[0578] C₂₃H₂₃N₃O₄.0·5H2O requires C, 66.7; H, 5.8; N, 10.1%.

EXAMPLE 14

[0579]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-carboxybenzamide

[0580] A 2N sodium hydroxide solution (0.27 ml)was added to a stirredsuspension ofN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-methoxycarbonylbenzamide(0.077 g) in a mixture of methanol (10 ml) and water (2 ml). Thereaction mixture was stirred at ambient temperature for 16 hours. Themixture was evaporated and the residue was dissolved in water. Theaqueous solution was and extracted with ethyl acetate, acidified to pH 5by the addition of dilute hydrochloric acid and extracted with ethylacetate. The resultant organic extract was evaporated and the residuewas dried at 40° C. There was thus obtained the title compound (0.006g); Mass Spectrum: M−H⁻ 416.

EXAMPLE 15

[0581]N-[5-(4-morpholinomethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0582] Morpholine (0.03 ml) was added to a stirred suspension ofN-[5-(4-chloromethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide(0.15 g) and potassium carbonate (0.094 g) in acetone (10 ml). Themixture was heated to 54° C. and stirred for 16 hours. The resultantsolution was evaporated and the residue was dissolved in methylenechloride. The organic solution was washed with water and evaporated. Theresidue was triturated under a mixture of ethyl acetate and diethylether. The resultant white solid was isolated and dried under vacuum at40° C. There was thus obtained the title compound (0.135 g); NMRSpectrum: (DMSOd₆) 2.18 (s, 3H), 2.35 (t, 2H), 3.28 (s, 2H), 3.55 (t,4H), 3.82 (s, 6H), 7.07 (d, 1H), 7.21 (d, 1H), 7.43 (d, 2H), 7.55 (m,2H), 7.61 (d, 1H), 7.81 (s, 1H), 7.89 (d, 2H), 9.78 (s, 1H), 10.16 (s,1H); Mass Spectrum: M+H⁺ 490.

[0583] TheN-[5-(4-chloromethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamideused as a starting material was prepared as follows:—

[0584] 4-Chloromethylbenzoyl chloride (0.73 g) was added dropwise to astirred mixture of N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (1g), triethylamine (0.98 ml) and methylene chloride (80 ml) and themixture was stirred at ambient temperature for 16 hours. A 1Nhydrochloric acid solution (10 ml) was added and the resultant solutionwas stirred at ambient temperature for 1 hour. The resultant white solidwas filtered off, washed with water and with diethyl ether, dried undervacuum at 40° C. to give the required starting material (1.35 g); NMRSpectrum: (DMSOd₆) 2.18 (s, 3H), 3.82 (s, 6H), 4.82 (s, 2H), 7.06 (d,1H), 7.21 (d, 1H), 7.58 (m, 5H), 7.81 (s, 1H), 7.94 (d, 2H), 9.76 (s,1H), 10.23 (s, 1H);

[0585] Mass Spectrum: M+H⁺ 439.

EXAMPLE 16

[0586]N-{5-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-2-methylphenyl}-3,4-dimethoxybenzamide

[0587] Using an analogous procedure to that described in Example 15,1-methylpiperazine was reacted withN-[5-(3-chloromethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide togive the title compound in 17% yield; NMR Spectrum: (DMSOd₆) 2.14 (s,3H) 2.18 (s, 3H),2.36 (m, 8H), 3.51 (s, 2H), 3.82 (s, 6H), 7.07 (d, 1H),7.22 (d, 1H), 7.47 (m, 2H), 7.61 (m, 3H), 7.82 (m, 31H) 9.75 (s, 1H),10.18 (s, 1H); Mass Spectrum: M+H⁺ 503.

[0588] TheN-[5-(3-chloromethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamideused as a starting material was prepared as follows:—

[0589] 3-Chloromethylbenzoyl chloride (0.6 g) was added to a stirredmixture of N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (1 g),triethylamine (0.98 ml) and methylene chloride (100 ml) and theresultant mixture was stirred at ambient temperature for 16 hours. Themixture was washed with 1N hydrochloric acid and with a saturatedaqueous solution of sodium bicarbonate, dried (MgSO₄) and evaporated.The residue was triturated under a mixture of ethyl acetate and diethylether. The resultant white solid was isolated and dried under vacuum at40° C. to give the required starting material (1.35 g); NMR Spectrum:2.19 (s, 3H), 3.82 (s, 6H), 4.84 (s, 2H), 7.06 (d, 1H), 7.23 (d, 1H),7.57 (m, 5H), 7.8 (s, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 9.76 (s, 1H), 10.26(s, 1H); Mass Spectrum: M+H⁺ 439.

EXAMPLE 17

[0590]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxybenzamide

[0591] 4-Methoxybenzoyl chloride (0.064 ml) was added to a stirredmixture of N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide (J. Med.Chem., 1996, 39 3343-3356; 0.13 g), triethylamine (0.14 ml) andmethylene chloride (5 ml) and the mixture was stirred at ambienttemperature for 16 hours. The resultant mixture was washed in turn witha 5% aqueous citric acid solution, with a saturated aqueous solution ofsodium bicarbonate and with brine, dried (MgSO₄) and evaporated. Theresidue was triturated under a mixture of ethyl acetate and isohexane.The resultant solid was isolated and dried under vacuum at 40° C. Therewas thus obtained the title compound (0.159 g); NMR Spectrum: (DMSOd₆)0.89 (m, 2H), 1.19 (m, 4H), 1.47 (m, 2H), 1.66 (m, 5H), 2.13 (s, 3H),2.3 (t, 2H), 3.82 (s, 3H), 7.03 (d, 2H), 7.12 (d, 1H), 7.37 (d, 1H),7.61 (s, 1H), 7.93 (d, 2H), 9.67 (s, 1H), 9.8 (s, 1H); Mass Spectrum:M+H⁺ 395.

EXAMPLE 18

[0592] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetylbenzamide

[0593] A solution of oxalyl chloride (0.1 ml) in methylene chloride (0.5ml) was added to a stirred mixture of 4-acetylbenzoic acid (0.098 g),DMF (3 drops) and methylene chloride (2 ml). The reaction mixture wasstirred and heated to 40° C. for 3 hours. The mixture was evaporated todryness. The residue was dissolved in methylene chloride (2 ml). DMF (3drops) was added, followed by the addition of a mixture ofN-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide (0.138 g) andpyridine (0.2 ml) in methylene chloride (4 ml). The resultant mixturewas stirred at ambient temperature for 18 hours. The reaction mixturewas evaporated and the residue was triturated under ethyl acetate. Theresultant solid was washed with water and dried to give the titleproduct (0.153 g); NMR Spectrum: (DMSOd₆) 0.8 (m, 2H), 1.1 (m, 4H), 1.39(m, 2H), 1.60 (m, 5H) 2.08 (s, 3H), 2.2 (t, 2H), 2.53 (s, 3H), 7.06 20(d, 1H), 7.28 (m, 1H), 7.56 (d, 1H), 7.86 (m, 1H), 7.97 (s, 4H), 8.37(m, 1H), 8.77 (m, 1H), 9.74 (s, 1H), 9.92 (s, 1H); Mass Spectrum: M+H⁺407.

EXAMPLE 19

[0594] Using an analogous procedure to that described in Example 17 orExample 18, the appropriate benzoyl chloride was reacted with theappropriate aniline to give the compounds described in Table II. TABLEII

No. (R¹)_(m) Method Note 1 4-ethoxy Ex. 17 a 2 4-butoxy Ex. 18 b 33,4-dimethoxy Ex. 17 c 4 3,5-dimethoxy Ex. 18 d 5 3,4-diethoxy Ex. 17 e6 3,4,5-trimethoxy Ex. 17 f 7 3-methoxycarbonyl Ex. 18 g 8 3-cyano Ex.18 h 9 4-cyano Ex. 17 i 10 3-methoxy-4-hydroxy Ex. 18 j 112-nitro-4-methoxy Ex. 18 k

EXAMPLE 20

[0595]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-carboxybenzamide

[0596] A 2N sodium hydroxide solution (0.27 ml) was added to a stirredsuspension ofN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide(0.087 g) in a mixture of methanol (10 ml) and water (2 ml). Thereaction mixture was stirred at ambient temperature for 16 hours. Themixture was evaporated and the residue was dissolved in water. Theaqueous solution was and extracted with ethyl acetate, acidified to pH 5by the addition of dilute hydrochloric acid and extracted with ethylacetate. The resultant organic extract was evaporated and the residuewas dried at 40° C. There was thus obtained the title compound (0.016g); NMR Spectrum: (DMSOd₆) 0.91 (m, 2H), 1.16 (m, 4H), 1.47 (m, 2H),1.66 (m, 5H), 2.15 (s, 33H), 2.28 (t, 2H), 7.15 (d, 1H), 7.36 (d, 1H),7.64 (s, 1H), 8.06 (d, 4H), 9.82 (so 1H), 10.04 (s, 1H); Mass Spectrum:M−H⁻ 407.

[0597] TheN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamideused as a starting material was obtained as follows:—

[0598] 4-Methoxycarbonylbenzoyl chloride (0.198 g) was added to astirred mixture of N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide(0.13 g), 4-dimethylaminopyridine (0.06 g), triethylamine (0.139 ml) andmethylene chloride (10 ml) and the mixture was stirred at ambienttemperature for 16 hours. The resultant precipitate was filtered off andwashed in turn with methylene chloride, ethyl acetate and 1Nhydrochloric acid. The solid was dried under vacuum at 40° C. to givethe title product (0.105 g); NMR Spectrum: (DMSOd₆) 0.78 (m, 2H), 1.14(m, 4H), 1.25 (m, 2H), 1.53 (m, 5H), 2.15 (so 3H) 2.28 (t, 2H), 3.88 (s,3H), 7.15 (d, 1H), 7.37 (d 2H), 7.64 (s, 1I), 8.07 (s, 4H), 9.82 (s,1H), 10.05 (s, 1H);

[0599] Mass Spectrum: M+H⁺ 432

EXAMPLE 21

[0600]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-carboxybenzamide

[0601] Using an analogous procedure to that described in Example 20,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-methoxycarbonylbenzamidewas hydrolysed to give the title compound in 16% yield; Mass Spectrum:M−H⁻ 407.

EXAMPLE 22

[0602]N-[5-(5-cyclohexylpentanoamido)-2-methylphenyl]-4-hydroxybenzamide

[0603] A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.096 g) in methylene chloride (3 ml) was added to astirred mixture of N-(5-amino-2-methylphenyl)-4-hydroxybenzamide (0.13g), 5-cyclohexylpentanoic acid (0.092 g) and DMF (0.5 ml) and thereaction mixture was stirred at ambient temperature for 5 hours. Themixture was evaporated and the residue was partitioned between ethylacetate and 1N hydrochloric acid solution. The organic phase wasevaporated to give the title compound (0.083 g);

[0604] NMR Spectrum: (DMSOd₆) 0.85 (m, 2H), 1.2 (m, 8H), 1.65 (m, 7H)2.15 (s, 3H), 2.28 30 (t, 2H), 6.86 (d, 2H), 7.14 (d, 1H), 7.3 (m, 1H),7.62 (d, 1H), 7.86 (d, 2H), 9.54 (s, 1H), 9.77 (s, 1H), 10.01 (s, 1H);Mass Spectrum: M+H⁺ 409.

EXAMPLE 23

[0605] The following compounds are described in J. Med. Chem., 1996, 39,3343-3356 and were prepared using analogous procedures. The compoundspossess p38 kinase inhibitory activity.

[0606]N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide;

[0607]N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide;

[0608]N-[5-(3-cyclohexylpropionamido)-2-inethylphenyl]-4-hydroxybenzamide; and

[0609] N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-aminobenzamide.

EXAMPLE 24

[0610]N-[5-(4-Cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide

[0611] 4-Cyclohexylbutyric acid (255 mg) was added to a solution ofN-(5-amino-2-methylphenyl)-4-hydroxybenzamide (242 mg) in DMF (3.0 ml).The mixture was stirred and a solution of1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (287 mg)added. The mixture was stirred overnight at ambient temperature,evaporated to a small volume and ethyl acetate (5 ml) was added. Themixture was washed with aqueous sodium bicarbonate solution (5 ml),water (5 ml), 2M aqueous hydrochloric acid (5 ml), water (5 ml) andbrine (5 ml). The organic phase was filtered through a megabond elutecolumn, eluting with ethyl acetate (25 ml) and evaporated to dryness.The residue was triturated with ether, filtered, washed with ether anddried to give the title compound (280 mg), m.p. 159-160° C.;

[0612] NMR Spectrum: (DMSOd₆) 0.75-1.0 (m, 2H), 1.05-1.35 (m, 6H),1.5-1.78 (m, 7H), 2-18 (s, 3H), 2.27 (t, 2H), 6.86 (d, 2H), 7.14 (d,1H), 7.39 (m, 1H), 7.63 (d, 1H), 7.86 (d, 2H), 9.56 (s, 1H), 9.7 (s,1H), 10.0 (s, 1H); Mass Spectrum: M+H⁺ 395, (M+Na)⁺ 417;

[0613] Microanalysis: % Theory C, 73.1; H, 7.66; N, 7.1%, % Found C,73.3; H, 7.7; N, 7.0%.

EXAMPLE 25

[0614]N-[2-methyl-5-(3-trifluoromethylbenzamido)phenyl]-3,4-dimethoxybenzamide

[0615] Phosphoryl chloride (0.045 ml) was added to a stirred solution ofN-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide (0.119 g) and3,4-dimethoxybenzoic acid (0.088 g) in pyridine (1 ml) which had beencooled to 0° C. The mixture was allowed to warm to ambient temperatureand was stirred for 16 hours. The resultant mixture was poured into a 2Naqueous hydrochloric acid solution. The resultant solid was isolated,washed with a saturated aqueous sodium bicarbonate solution and withisohexane and dried under vacuum at 55° C. There was thus obtained thetitle compound (0.107 g); NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 3.82 (s,6H), 7.07 (d, 1H), 7.23 (d, 1H), 7.60 (m, 3H), 7.77 (m, 2H), 7.95 (d,1H), 8.27 (m, 2H), 9.76 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M−H⁻ 457.

[0616] The N-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide used asstarting material was prepared by the reaction of3-trifluoromethylbenzoyl chloride with 4-methyl-3-nitroaniline andreduction of the resultant product using analogous procedures to thosedescribed in the portion of Example 8 which is concerned with thepreparation of starting materials.

EXAMPLE 26

[0617]N-[5-(3-morpholinomethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0618] Using an analogous procedure to that described in Example 15,morpholine was reacted withN-[5-(3-chloromethylbenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide togive the title compound in 84% yield; NMR Spectrum: (DMSOd₆) 2.18 (s,3H), 2.37 (t, 4H), 3.52 (s, 2H), 3.56 (t, 4H), 3.82 (s, 6H), 7.07 (d,1H), 7.21 (d, 1H), 7.43-7.59(m, 2H), 7.52-7.64 (m, 3H), 7.79 (s, 1H)7.89 (d, 2H), 9.78 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+H⁺ 490.

EXAMPLE 27

[0619]N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-morpholinomethylbenzamide

[0620] A mixture ofN-[5-(4-cyanobenzamido)-2-methylphenyl]-4-chloromethylbenzamide (0.1 g),morpholine (0.033 g), potassium carbonate (0.068 g) and acetone (5 ml)was stirred and heated to 55° C. for 16 hours. The reaction mixture wasevaporated and the residue was triturated under water. The solid soobtained was isolated and dried under vacuum at 55° C. There was thusobtained the title compound (0.099 g); NMR Spectrum: (DMSOd₆) 2.2 (s,31H), 2.38 (m, 4H), 3.52 (s, 2H), 3.58 (t, 4H), 7.23 (d, 1H), 7.45 (d,2H), 7.57 (d, 1H), 7.82 (d, 1H), 7.93 (d, 2H), 8.0 (d, 2H), 8.1 (d, 2H),9.85 (s, 1H), 10.45 (s, 1H);

[0621] Mass Spectrum: M−H⁻ 453.

[0622] TheN-[5-(4-cyanobenzamido)-2-methylphenyl]-4-chloromethylbenzamide used asa material was obtained as follows:—

[0623] Triethylamine (1.83 ml) was added to a stirred mixture ofN-(3-amino-4-methylphenyl)-4-cyanobenzamide (3.0 g),4-chloromethylbenzoyl chloride (2.48 g), 4-dimethylaminopyridine (0.146g) and methylene chloride (50 ml) and the reaction mixture was stirredat ambient temperature for 16 hours. The mixture was evaporated and theresidue was triturated under 2N aqueous hydrochloric acid solution. Thesolid so obtained was isolated, washed in turn with a saturated aqueoussodium bicarbonate solution, water and isohexane and dried under vacuumat 55° C. There was thus obtained the required compound (4.76 g); NMRSpectrum: (DMSOd₆) 2.2 (s, 3H), 4.84 (s, 2H), 7.25 (d, 1H), 7.57 (d,3H). , 1H), 7.98 (m, 4H), 8.1 (d, 2H), 9.93 (s, 1H), 10.46 (s, 1H);

[0624] Mass Spectrum: M−H⁻ 402.

EXAMPLE 28

[0625] Using an analogous procedure to that described in Example 27, theappropriate amine was reacted with the appropriate benzyl chloride togive the compounds described in Table III. TABLE III

No. (R¹)_(m) R Note 1 3-(piperazin-1-yl)methyl hydrogen a 23-(4-propylpiperazin-1-yl)methyl hydrogen b 33-(4-carbamoylpiperidin-1-yl)methyl hydrogen c 44-(4-methylhomopiperazin-1-yl)methyl hydrogen d 53-(4-acetylpiperazin-1-yl)methyl 3-trifluoromethyl e 64-(4-ethylpiperazin-1-yl)methyl 3-trifluoromethyl f 74-(4-methylpiperazin-1-yl)methyl 4-cyano g 83-(4-isopropylpiperazin-1-yl)methyl 4-cyano h 93-(pyrrolidin-1-yl)methyl 4-cyano i 10 3-morpholinomethyl 4-cyano j 114-piperidinomethyl 4-cyano k 12 4-(piperazin-1-yl)methyl 4-cyano l 134-(4-methylpiperazin-1-yl)methyl 4-cyano m

[0626] The N-(5-benzamido-2-methylphenyl)-3-chloromethylbenzamide usedas a starting material was prepared as follows:

[0627] Triethylamine (2.0 ml) was added to a stirred mixture ofN-(3-amino-4-methylphenyl)benzamide (3.0 g), 3-chloromethylbenzoylchloride (2.76 g), 4-dimethylaminopyridine (0.162 g) and methylenechloride (50 ml) and the reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue wastriturated under 2N aqueous hydrochloric acid solution. The solid soobtained was isolated, washed in turn with a saturated aqueous sodiumbicarbonate solution, water and isohexane and dried under vacuum at 55°C. There was thus obtained the required compound (5.1 g) which was usedwithout further purification;

[0628] NMR (DMSOd₆) 2.19 (s, 3H), 4.85 (s, 2H), 7.23 (d, 1H), 7.55 (m,5H), 7.66 (d, 1H), 7.84 (s 1H), 7.95 (m, 3H), 8.05 (s, 1H), 9.96 (s,1H), 10.22 (s, 1H); Mass M−H 377.

[0629] b) The product gave the following data: NMR (DMSOd₆) 0.91 (t,3H), 1.40 (m, 2H), 2.19 (m, 5H), 2.37 (br s, 8H), 3.53 (s, 2H), 7.21 (d,1H), 7.52 (m, 6H), 7.84 (m, 3H), 7.95 (d, 2H); Mass M−H 469.

[0630] c) The product gave the following data: NMR (DMSOd₆) 1.6 (m, 4H),1.98 (m, 3H), 2.2 (s, 3H), 2.82 (br d, 2H), 3.51 (s, 2H), 6.65 (br s,1H), 7.17 (br s, 1H), 7.21 (d, 1H), 7.52 (m, 6H), 7.83 (m, 3H), 7.95 (d,2H); Mass M−H 469.

[0631] d) The product gave the following data: NMR (DMSOd₆) 1.7 (m, 2H),2.2 (s, 3H), 2.24 (s, 3H), 2.58 (m, 8H), 3.66 (s, 2H), 7.21 (d, 1H),7.52 (m, 6H), 7.83 (m, 1H), 7.95 (m, 4H); Mass M−H 455.

[0632] The N-(5-benzamido-2-methylphenyl)-4-chloromethylbenzamide usedas a starting material was prepared as follows:

[0633] Triethylamine (2.0 ml) was added to a stirred mixture ofN-(3-amino-4-methylphenyl)benzamide (3.0 g), 4-chloromethylbenzoylchloride (2.76 g) 4-dimethylaminopyridine (0.162 g) and methylenechloride (50 ml) and the reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue wastriturated under 2N aqueous hydrochloric acid solution. The solid soobtained was isolated, washed in turn with a saturated aqueous sodiumbicarbonate solution, water and isohexane and dried under vacuum at 55°C. There was thus obtained the required compound (4.96 g), NMR (DMSOd₆)2.19 (s, 3H), 4.84 (s, 2H), 7.22 (d, 1H), 7.54 (m, 6H), 7.84 (s, 1H),7.96 (m, 4H), 9.92 (s, 1H), 10.22 (s, 1H); Mass M−H 377.

[0634] e) The product gave the following data: NMR (DMSOd₆) 1.97 (s,3H), 2.2 (s, 3H), 2-38 (m, 4H), 3.28 (br s, 2H), 3.42 (br s, 2H), 3.56(s, 2H), 7.22 (d, 1H), 7.5 (m, 3H), 7.75 (t, 1H), 7.81 (s, 1H), 7.91 (m,3H), 8.28 (m, 2H); Mass M−H 537.

[0635] TheN-[5-(3-trifluoromethylbenzamido)-2-methylphenyl]-3-chloromethylbenzamideused as a starting material was prepared as follows:

[0636] A mixture of 3-trifluoromethylbenzoyl chloride (9.9 ml),3-nitro-4-methylaniline (10 g) and pyridine (100 ml) was stirred andheated to 80° C. for 2 hours. The reaction mixture was evaporated andthe residue was triturated under 2N aqueous hydrochloric acid solution.The solid so obtained was isolated, washed in turn with a saturatedaqueous sodium bicarbonate solution, water and isohexane and dried undervacuum at 55° C. to giveN-(4-methyl-3-nitrophenyl)-3-trifluoromethylbenzamide as a solid (21.9g); NMR (DMSOd₆) 7.49 (d, 1H), 7.78 (m, 1H), 7.99 (m, 2H), 8.27 (m, 2H),8.51 (s, 1H), 10.77 (s, 1H); Mass M−H 323.

[0637] Palladium on charcoal (1.0 g) was added to a solution of aportion (10 g) of the material so obtained in methanol (250 ml).Ammonium formate (19.0 g) was added and the resultant mixture wasstirred and heated to reflux for 1 hour. The mixture was filteredthrough diatomaceous earth (Celite®) and the filtrate was evaporated.The residue was triturated under water. The resultant solid was isolatedand dried under vacuum at 55° C. to giveN-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide as a solid (7.98g): NMR (DMSOd₆) 2.01 (s, 3H), 4.83 (s, 2H), 6.85 (m, 2H), 7.08 (s, 1H),7.74 (t, 1H), 7.92 (d, 1H), 8.2 (d, 1H), 10.11 (s, 1H); Mass M−H 293.

[0638] Triethylamine (1.6 ml) was added to a stirred mixture of aportion (3.0 g) of S the material so obtained, 3-chloromethylbenzoylchloride (2.17 ml), 4-dimethylaminopyridine (0.125 g) and methylenechloride (50 ml) and the reaction was stirred at ambient temperature for16 hours. The mixture was evaporated and the residue was trituratedunder 2N aqueous hydrochloric acid solution. The solid so obtained wasisolated, washed in turn with a saturated aqueous sodium bicarbonatesolution, water and isohexane and dried under vacuum at 55° C. There wasthus obtained the required compound as a solid (5.17 g); NMR (DMSOd₆)2.2 (s, 3H), 4.85 (s, 2H), 7.25 (d, 1H), 7.6 (m, 3H), 7.8 (m, 2H), 7.95(d, 2H), 8.05 (s, 1H), 8.16 (ma 2H), 9.96 (s, 1H)_(n 10.44) (s, 1H);Mass M−H 445.

[0639] f) The product gave the following data: NMR (DMSOd₆) 0.97 (t,3H), 2.2 (s, 3H), 2.35 (m, 10H), 3.53 (s, 2H), 7.23 (d, 1H), 7.42 (d,2H), 7-59 (d, 1H), 7.78 (m, 2H), 7.93 (m, 3H), 8.26 (m, 2H); Mass M−H524.

[0640] TheN-[5-(3-trifluoromethylbenzamido)-2-methylphenyl]-4-chloromethylbenzamideused as a starting material was prepared as follows:

[0641] Triethylamine (1.6 ml) was added to a mixture ofN-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide (3 g),4-chloromethylbenzoyl chloride (2.9 g), 4-dimethylaminopyridine (0.125g) and methylene chloride (50 ml) and the reaction mixture was stirredat ambient temperature for 16 hours. The mixture was evaporated and theresidue was triturated under 2N aqueous hydrochloric acid solution. Thesolid so obtained was isolated, washed in turn with a saturated aqueoussodium bicarbonate solution, water and isohexane and dried under vacuumat 55° C. There was thus obtained the required compound as a solid (5.07g); NMR (DMSOd₆) 2.21 (s, 3H), 4.84 (s, 2H), 7.25 (d, 1H), 7.57 (m, 3H),7.76 (t, 1H), 7.83 (d, 1H), 7.96 (m, 3H), 8.26 (m, 2H), 9.92 (s, 1H),10.44 (s, 1H); Mass M−H 445.

[0642] g) The product gave the following data: NMR (DMSOd₆) 2.14 (s,3H), 2.2 (s, 3H), 2.36 (m, 8H), 3.51 (s, 2H), 7.23 (d, 1H), 7.46 (m,2H), 7.58 (m, 1H), 7.84 (In, 3H), 8.0 (d, 2H), 8.1 (d, 2H); Mass M−H⁻467.

[0643] TheN-[5-(4-cyanobenzamido)-2-methylphenyl]-3-chloromethylbenzamide used asa starting material was prepared as follows:

[0644] Triethylamine (1.83 ml) was added to a mixture ofN-(3-amino-4-methylphenyl)-4-cyanobenzamide (3 g), 3-chloromethylbenzoylchloride (2.48 g), 4-dimethylaminopyridine (0.146 g) and methylenechloride (50 ml) and the reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue wastriturated under 2N aqueous hydrochloric acid solution. The solid soobtained was isolated, washed in turn with a saturated aqueous sodiumbicarbonate solution, water and isohexane and dried under vacuum at 55°C. There was thus obtained the required compound as a solid (4.76 g);NMR (DMSOd₆) 2.2 (s, 3H), 4.84 (s, 2H), 7.24 (d, 1H), 7.55 (m, 2H), 7.66(d 1H), 7.83 (d, 1H), 8.0 (m, 4H), 8.1 (d, 2H), 9.96 (s, 1H), 10.46 (s,1H); Mass M−H 402.

[0645] h) The product gave the following data: NMR (DMSOd₆) 0.92 (d,6H), 2.2 (s, 3H), 2.39 (m, 8H), 2.58 (m, 1H), 3.5 (s, 2H), 7.22 (d, 1H),7.45 (m, 2H), 7.56 (d, 1H), 7.85 (m, 3H), 8.0 (d, 2H), 8.11 (d, 2H);Mass M−H 494.

[0646] TheN-[5-(4-cyanobenzamido)-2-methylphenyl]-4-chloromethylbenzamide used asa starting material was prepared by the reaction ofN-(3-amino-4-methylphenyl)-4-cyanobenzamide and 4-chloromethylbenzoylchloride using an analogous procedure to that described in Note g)immediately hereinbefore.

[0647] i) The product gave the following data: NMR (DMSOd₆) 1.71 (br s,4H), 2.2 (s, 3H), 2.46 (m, 4H), 3.63 (s, 2H), 7.23 (d, 1H), 7.47 (m,2H), 7.59 (m, 1H), 7.85 (m, 3H), 7.99 (d, 2H), 8.12 (d, 2H); Mass M−H437.

[0648] j) The product gave the following data: NMR (DMSOd₆) 2.2 (s, 3H),2.38 (m, 4H), 3.52 (s, 2H), 3.58 (t, 4H), 7.13 (d, 1H), 7.5 (m, 3H),7.85 (m, 3H), 8.0 (d, 2H), 8.1 (d, 2H); Mass M−H 453.

[0649] k) The product gave the following data: NMR (DMSOd₆) 1.38 (br s,2H), 1.48 (br s, 4H), 2.2 (s, 3H), 2.32 (br s, 4H), 3.5 (s, 2H), 7.23(d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.84 (s, 1H), 7.95 (d, 2H), 8.01(d, 2H), 8.13 (d, 2H), 9.84 (br s, 1H), 10.47 (br s, 1H); Mass M−H 452.

[0650] l) The product gave the following data: NMR (DMSOd₆) 2.2 (s, 3H),2.3 (m, 4H), 2.66 (m, 4H), 3.48 (s, 2H), 7.23 (d, 1H), 7.42 (d, 2H),7.57 (d, 1H), 7.82 (s, 1H), 7.91 (d, 2H), 8.0 (d, 2H), 8.1 (d, 2H), 9.84(s, 1H), 10.47 (s, 1H); Mass M−H 453.

[0651] m) The product gave the following data: NMR (DMSOd₆) 2.12 (s,3H), 2.19 (s, 3H), 2.36 (m, 8H), 3.51 (s, 2H), 7.22 (d, 1H), 7.42 (d,2H), 7.58 (m, 1H), 7.81 (d, 1H), 7.92 (d, 2H), 7.99 (d, 2H), 8.1 (d,2H); Mass M−H 466.

EXAMPLE 29

[0652] N-[5-(2-hydroxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide

[0653] Using an analogous procedure to that described in Example 10,Nh-[5-(2-benzyloxybenzamido)-2-methylphenyl]-3.4-dimethoxybenzamide washydrogenolysed to give the title compound in 92% yield;

[0654] NMR Spectrum: (DMSOd₆) 2.19 (s, 3H), 3.82 (s, 6H), 6.94 (m, 2H),7.06 (d, 1H), 7.24 (d, 1H), 7.42 (t 1H), 7.47 (m, 1H), 7.53 (d, 1H),7.62 (m, 2H), 7.76 (d, 1H), 7.96 (m, 1H), 9.75 (br s, 1H), 10.35 (br s,1H), 11.83 (br s, 1H); Mass Spectrum: M−H⁻ 405.

[0655] TheN-[5-(2-benzyloxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide usedas a starting material was obtained by the reaction ofN-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide and 2-benzyloxybenzoylchloride (obtained by the reaction of 2-benzyloxybenzoic acid and oxalylchloride) using an analogous procedure to that described in Example 6.There was thus obtained the title compound in 64% yield; NMR Spectrum:(DMSOd₆) 2.13 (s, 3H), 3.83 (s, 6H), 5.24 (s, 2H), 7.11 (m, 3H), 7.26(m, 3H), 7.52 (m, 4H), 7.63 (m, 2H), 7.71 (m, 1H), 7.86 (t, 2H), 9.73(br s, 1H), 10.13 (d, 1H); Mass Spectrum: M+H⁺ 497.

EXAMPLE 30

[0656]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-hydroxybenzamide

[0657] Using an analogous procedure to that described in Example 10,N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-benzyloxybenzamide washydrogenolysed to give the title compound in 69% yield, m.p. 234-238°C.;

[0658] NMR Spectrum: (DMSOd₆) 2.22 (s, 3H), 2.97 (s, 6H), 6.92 (m, 3H),7.21 (m, 3H), 7.3 (m, 1H), 7.42 (m, 1H), 7.57 (m, 1H), 8.02 (m, 1H),8.21 (d, 1H), 10.15 (s, 1H), 10.38 (m, 1H);

[0659] Mass Spectrum: M+H⁺ 390.

[0660] TheN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-benzyloxybenzamideused as a starting material was obtained by the reaction ofN-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide and2-benzyloxybenzoyl chloride using an analogous procedure to thatdescribed in Example 7. There was thus obtained the title compound. m.p.136-139° C.;

[0661] NMR Spectrum: (DMSOd₆) 1.85 (s, 1H), 2.98 (s, 6H), 5.36 (s, 2H),6.9 (d, 1H), 7.12 (m, 2H), 7.33 (m, 7H), 7.52 (m, 4H), 7.9 (d, 1H), 8.12(s, 1H), 9.7 (s, 1H), 10.08 (s, 1H);

[0662] Mass Spectrum: M+H⁺ 480.

EXAMPLE 31

[0663] N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-aminobenzamide

[0664] 10% Palladium-on-carbon (0.3 g) was added to a stirred suspensionof N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-nitrobenzamide(2.25 g) in methanol (300 ml) and the mixture was stirred under anatmosphere of hydrogen. After cessation of hydrogen uptake, the mixturewas filtered and the filtrate was evaporated. The solid so obtained wasdried under vacuum at 60° C. There was thus obtained the title compound(1.8 g); NMR Spectrum: (DMSO d₆) 2.18 (s, 3H), 2.95 (s, 6H), 5.26 (br s,2H), 6.73 (m, 1H), 6.89 (m, 1H), 7.15 (m, 3H), 7.21 (m, 3H), 7.27 (m,1H), 7.57 (m, 1H), 7.77 (d, 1H), 9.63 (br s, 1H), 10.07 (br s, 1H); MassSpectrum: M+H⁺ 390.

EXAMPLE 32

[0665]N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-acetamidobenzamide

[0666] Acetyl chloride (0.066 g) was added to a stirred mixture ofN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-aminobenzamide (0.3g), triethylamine (0.22 ml) and methylene chloride (10 ml) and themixture was stirred at ambient temperature for 60 hours. The mixture waswashed with a saturated aqueous sodium bicarbonate solution and withwater, dried (MgSO₄) and evaporated. The resultant solid was dried undervacuum at 60° C. There was thus obtained the title compound (0.243 g),m.p. 178-179° C.;

[0667] NMR Spectrum: (DMSO d₆) 2.05 (s, 3H), 2.19 (s, 3H), 2.95 (s, 6H),6.9 (m, 1H), 7.24 (m, 3H), 7.29 (t, 1H), 7.42 (t, 1H), 7.57 (m, 1H),7.61 (m, 1H), 7.79 (d, 1H), 7.81 (m, 1H), 8.09 (d, 1H), 9.86 (s, 1H),10.09 (m, 2H); Mass Spectrum: M+H⁺ 432.

EXAMPLE 33

[0668]N-[5-(3-acetamidobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide 2429

[0669] Using an analogous procedure to that described in Example 32,acetyl chloride was reacted withN-[5-(3-aminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide to givethe title compound in 69% yield, m.p. 187-188° C.;

[0670] NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.18 (s, 3H), 3.92 (s, 6H),7.06 (d, 1H), 7.21 (d, 1H), 7.42 (t, 1H), 7.58 (m, 4H), 7.8 (m, 1H),8.05 (m, 1H), 9.77 (s, 1H), 10.1 (s, 1H), 10.21 (s, 1H); Mass Spectrum:M+H⁺ 448.

EXAMPLE 34

[0671] Pharmaceutical Compositions

[0672] The following illustrate representative pharmaceutical dosageforms of the invention as defined herein (the active ingredient beingtermed “(Compound X”), for therapeutic or prophylactic use in humans:(a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II Compound X 50 Lactose Ph. Eur223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone(5% w/v paste) 2.25 Magnesium stearate 3.0 (c) Tablet III Compound X 1.0Lactose Ph. Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5%w/v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X10 Lactose Ph.Eur 488.5 Magnesium 1.5 (e) Injection I (50 mg/ml)Compound X 5.0% w/v 1 M Sodium hydroxide solution 15.0% v/v 0.1 MHydrochloric acid (to adjust pH to 7.6) 4.5% w/v Polyethylene glycol 400Water for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0%w/v Sodium phosphate BP 3.6% w/v 0.1 M Sodium hydroxide solution 15.0%v/v Water for injection to 100% (g) Injection III (1 mg/ml. buffered topH6) Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38%w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100% (h)Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate 13.5Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 (i) AerosolII Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (l) Ointment ml Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml # acetate phthalate. The aerosol formulations (h)-(k) may beused in conjunction with standard, metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid.

1. The use of a compound of the Formula I

wherein: R¹ and R² which may be the same or different are selected fromhydroxy C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulphonyl,arylsulphonyl, C₁₋₆alkylaminosulphonyl, di-(C₁₋₆alkyl)aminosulphonyl,nitro, cyano, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,C₁₋₆alkanoylamino, C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo, trifluoromethyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkoxy, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl andheterocyclylC₁₋₆alkyl; m and p, are independently 0-3, and when m and/orp is 2 or 3 each R group may be the same or different; R³ is C₁₋₄alkyl;q is 0-4; R⁴ is aryl or cycloalkyl wherein R⁴ is optionally substitutedwith up to 3 substituents having any value defined for R¹; or apharmaceutically-acceptable salt or in vivo cleavable ester thereof inthe manufacture of a medicament for use in the treatment of diseases ormedical conditions mediated by cytokines.
 2. A compound of the Formula Iaccording to claim 1 for use in a method of treatment of the human oranimal body by therapy except thatN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetoxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]benzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]4-hydroxymethylbenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-nitrobenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-aminobenzamide,N-[5-(2-cyclohexylacetamido)-2-methylphenyl]-4-acetoxybenzamide,N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(3-phenylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(2-bicyclo[2.2.1]hept-2-ylacetamido)-2-methylphenyl]-4-hydroxybenzamide,N-{5-[2-(3,4-dichlorophenyl)acetamido]-2-methylphenyl}-4-hydroxybenzamide,N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide,N-[5-(3-phenylpropionamido)-2-methylphenyl]-4-acetoxybenzamide andN-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-acetoxybenzamide areexcluded.
 3. A pharmaceutical composition which comprises an amidederivative of the Formula I, or a pharmaceutically-acceptable salt or invivo cleavable ester thereof, according to claim 2 in association with apharmaceutically-acceptable diluent or carrier.
 4. An amide derivativeof the Formula I according to claim 1 wherein R¹ is hydroxy, methoxy,ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino, dimethylamino,carboxy, methoxycarbonyl, nitro, cyano, acetamido, acetyl, acetoxy,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro,bromo, trifluoromethyl, pyrrolidin-1-yl, piperidino, morpholino,4-thiamorpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-methylhomopiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl; m is1, 2 or 3; p is 0; R³ is methyl; q is 0; and R⁴ is phenyl which isoptionally substituted with 1 or 2 substituents selected from hydroxy,methoxy, ethoxy, amino, methylamino, dimethylamino, methoxycarbonyl,nitro, cyano, acetamido, fluoro, chloro, bromo, trifluoromethyl, phenyl,benzyloxy, pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl.4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl; or apharmaceutically-acceptable salt thereof; except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]4-hydroxybenzamide,N-[5-(2-hydroxybenzamido)-2-methylphenyl]-2-hydroxybenzamide,N-[5-(4-methoxybenzamido)-2-methylphenyl]-4-methoxybenzamide,N-[5-(3-methoxycarbonylbenzamido)-2-methylphenyl]-3-methoxycarbonylbenzamideandN-[5-(4-methoxycarbonylbenzamido)-2-methylphenyl]-4-methoxycarbonylbenzamideare excluded.
 5. An amide derivative of the Formula I according to claim1 wherein R¹ is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy,amino, methylamino, dimethylamino, carboxy, methoxycarbonyl, nitro,cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, fluoro, chloro, bromo, trifluoromethyl,pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl; m is1, 2 or 3; p is 0; R³ is methyl; q is 1, 2, 3 or 4; and R⁴ iscyclopentyl or cyclohexyl; or a pharmaceutically-acceptable saltthereof; except thatN-[5-(3-cyclohexylpropionamido)-2-methylphenyl]4-hydroxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-acetoxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-3-hydroxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-2-hydroxybenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-methoxycarbonylbenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-nitrobenzamide,N-[5-(3-cyclohexylpropionamido)-2-methylphenyl]-4-aminobenzamide,N-[5-(2-cyclohexylacetamido)-2-methylphenyl]-4-acetoxybenzamideN-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-hydroxybenzamide,N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide andN-[5-(3-cyclopentylpropionamido)-2-methylphenyl]-4-acetoxybenzamide areexcluded.
 6. An amide derivative of the Formula I according to claim 1wherein R¹ is hydroxy methoxy, ethoxy, propoxy, isopropoxy, butoxy,carboxy, methoxycarbonyl, nitro, cyano, acetamido, acetyl, methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, bromo ortrifluoromethyl; m is 0-3 and when m is 2 or 3 each R¹ group is the sameor different; p is 0; R³ is methyl; q is 0; and R⁴ is phenyl which issubstituted at the 3- or 4-position with a substituent selected fromamino, methylamino, dimethylamino, aminomethyl, pyrrolidin-1-yl,piperidino, morpholino, 4-thiamorpholino, piperazin-1-yl,4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl; or apharmaceutically-acceptable salt thereof; except thatN-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide isexcluded.
 7. An amide derivative of the Formula I according to claim 1wherein R¹ is amino, methylamino, dimethylamino, aminomethyl,pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-]-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl or 4-methylhomopiperazin-1-ylmethyl; m is 1with the R¹ group located at the 3- or 4-position; p is 0; R³ is methyl;q is 0; and R⁴ is phenyl which is optionally substituted with 1 or 2substituents, which may be the same or different, selected from hydroxy,methoxy, ethoxy, carboxy, methoxycarbonyl, cyano, methyl, fluoro, chloroand trifluoromethyl; or a pharmaceutically-acceptable salt thereof. 8.An amide derivative of the Formula I according to claim 1 wherein R¹ isamino, methylamino, dimethylamino, aminomethyl, pyrrolidin-1-yl,piperidino, morpholino, 4-thiamorpholino, piperazin-1-yl,4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl or 4-methylhomopiperazin-1-ylmethyl; m is 1with the R¹ group located at the 3- or 4-position; p is 0; R³ is methyl;q is 0; and R⁴ is phenyl which is substituted at the 3- or 4-positionwith a substituent selected from amino, methylamino, dimethylamino,aminomethyl, pyrrolidin-1-yl, piperidino, morpholino, 4-thiamorpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl,4-carbamoylpiperidin-1-ylmethyl, morpholinomethyl,4-thiamorpholinomethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-propylpiperazin-1-ylmethyl, 4-isopropylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl and 4-methylhomopiperazin-1-ylmethyl; or apharmaceutically-acceptable salt thereof.
 9. A compound of the Formula Iaccording to claim 1 which is:—N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3,4,5-trimethoxybenzamide,and pharmaceutically-acceptable salts thereof.
 10. A compound of theFormula I according to claim 1 selected from:—N-(5-benzamido-2-methylphenyl)-3-(piperazin-1-yl)methylbenzamide,N-(5-benzamido-2-methylphenyl)-3-(4-methylpiperazin-1-yl)methylbenzamide,N-[2-methyl-5-(3-trifluoromethylbenzamido)phenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide,N-[5-(3-chlorobenzamido)-2-methylphenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide,N-[5-(2-methoxybenzamido)-2-methylphenyl]-3-(4-methylpiperazin-1-yl)methylbenzamideandN-[5-(3-ethoxybenzamido)-2-methylphenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide;and pharmaceutically-acceptable salts thereof.
 11. A compound of theFormula I according to claim 1 selected from:—N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-morpholinobenzamide andN-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-(4-methylpiperazin-1-yl)methylbenzamide;and pharmaceutically-acceptable salts thereof.
 12. A process for thepreparation of an amide derivative of the Formula I, or apharmaceutically-acceptable salt or in vivo cleavable ester thereof,according to claim 1 which comprises:— (a) the reaction of a compound ofthe Formula III

 with a compound of the Formula IV

or an activated derivative thereof, under standard amide bond formingconditions, wherein variable groups are as defined in claim 1 andwherein any functional group is protected, if necessary, and: i.removing any protecting groups; ii. optionally forming apharmaceutically-acceptable salt or in vivo cleavable ester; (b) thereaction of an acid of the Formula VI

or an activated derivative thereof, with an aniline of the Formula VIII

under standard amide bond forming conditions, wherein variable groupsare as defined in claim 1 and wherein any functional group is protected,if necessary, and: i. removing any protecting groups; ii. optionallyforming a pharmaceutically-acceptable salt or in vivo cleavable ester;(c) for the preparation of a compound of the Formula I according toclaim 1 wherein R¹ or a substituent on R⁴ is heterocyclylC₁₋₆alkyl, thereaction of a compound of the Formula I wherein R¹ or a substituent onR⁴ is a group of the formula —C₁₋₄alkyl-Z wherein Z is a displaceablegroup with a heterocyclyl compound; (d) for the preparation of acompound of the Formula I according to claim 1 wherein R¹, R² or asubstituent on R⁴ is carboxy, the cleavage of a compound of the FormulaI wherein R¹, R² or a substituent on R⁴ is C₁₋₆alkoxycarbonyl; (e) forthe preparation of a compound of the Formula I according to claim 1wherein R¹, R² or a substituent on R⁴ is hydroxy, the cleavage of acompound of the Formula I wherein R¹, R² or a substituent on R⁴ isbenzyloxy or substituted benzyloxy; (f) for the preparation of acompound of the Formula I according to claim 1 wherein R¹, R² or asubstituent on R⁴ is amino, the reduction of a compound of the Formula Iwherein R¹, R² or a substituent on R⁴ is nitro; or (g) for thepreparation of a compound of the Formula I according to claim 1 whereinR¹, R² or a substituent on R⁴ is C₁₋₆alkanoylamino, the acylation of acompound of the Formula I wherein R¹, R² or a substituent on R⁴ isamino.